Grants for Native American Tribal Organizations

Background The mission of the Office of Fossil Energy and Carbon Management (FECM) is to minimize the environmental impacts of fossil fuels while working towards net-zero emissions. FECMs programs use research, development, demonstration, and deployment approaches to advance technologies to reduce carbon emissions and other environmental impacts of fossil fuel production and use, particularly the hardest-to-decarbonize applications in the electricity and industrial sectors. Priority areas of technology work include point-source carbon capture, hydrogen with carbon management, methane emissions reduction, critical mineral production, and carbon dioxide removal to address the accumulated CO2 emissions in the atmosphere. FECM recognizes that global decarbonization through carbon dioxide removal (CDR) is essential to meeting climate goals and works to engage with international colleagues to leverage expertise in these areas. FECM is also committed to improving the conditions of communities impacted by the legacy of fossil fuel use and to supporting a healthy economic transition that accelerates the growth of good-paying jobs. The Office of Carbon Managements mission is to facilitate a just and environmentally sustainable transition toward a net-zero carbon economy. This mission focuses on the capture, storage, and containment of carbon dioxide. We address emissions associated with the power and industrial sectors, as well as legacy emissions in the atmosphere, and we seek to permanently store and/or convert carbon dioxide (CO2) to reduce negative climate impacts. Our actions center on investments in technological readiness and analysis. Our department researches a portfolio of carbon management approaches, with an emphasis on facilitating development of approaches that meet our technical, justice, and sustainability requirements for commercialization. Our goals are to improve their performance, reduce costs, and scale the deployment of the technologies to decarbonize the power and industrial sectors and to remove CO2 from the atmosphere. The Office of Carbon Management comprises two major offices: The Office of Carbon Management Technologies leads and invests in research, development, demonstration, and deployment across five divisions: Hydrogen with Carbon Management, Carbon Transport and Storage, Carbon Dioxide Removal, Carbon Conversion, and Point Source Carbon Capture. The Office of Policy, Analysis and Engagement leads in strategic activities and international and intra-governmental coordination across three divisions: Policy and Analysis, Engagement, and Federal Partnerships. FECMs Office of Resource Sustainability (ORS) administers the Departments technological development and approaches for reducing the environmental impacts of our historical and continued use of fossil fuels. Reducing the environmental impacts of fossil fuel infrastructure and reducing emissions throughout the supply chain is critical to achieving net-zero emissions. ORS supports a just transition to clean energy while minimizing the environmental impacts in sectors where fossil fuels are difficult to avoid. These goals are accomplished through policy, research, innovation, outreach, and stewardship. ORSs Office of Research Development advances technologies and solutions to reduce the environmental impacts and emissions associated with fossil energy development, use, transportation, and storage. Its Office of Regulation, Analysis, and Engagement regulates the import and export of natural gas, conducts analysis of fossil fuel and carbon markets, assesses policy and regulatory proposals, leads outreach for domestic and international engagements, and addresses environmental and energy justice impacts for communities most impacted by fossil fuel development and use. DOE will not accept questions at this time regarding issuance of the FOA. Details on how to submit questions and comments will be provided in the FOA, if issued. Technical Overview and Objectives Program Area 1: Carbon Management Technologies The U.S. energy portfolio and U.S. economy depend heavily on fossil fuels and other sources of GHG emissions today, spanning sectors like power generation, industry, heat and transportation fuels. Advancing clean energy, carbon capture with durable storage in both the power and industrial sectors and CDR are imperative for achieving net-zero GHG goals. FECM envisions enabling the demonstration and ultimately deployment of technologies for carbon management and mitigating challenges of fossil fuel use in a just and sustainable way, with the goal of achieving net-zero GHG emissions by mid-century. As previously stated, one of the key missions of the Office of Fossil Energy is to, minimize the environmental impacts of fossil fuels while working towards net-zero emissions. To accomplish this mission, it is imperative that FECM provide outreach and education to many stakeholders, including the general public in order to allow them to make educated choices about energy. Towards this end, FECM seeks to partner with organizations with similar goals to help improve understanding and develop cooperative action on CDRs by reaching out to additional international and national organizations to conduct a series of co-related tasks that mutually serve the mission of the public as well as FECM. These Areas of Interest are described below: Areas of Interest Area 1: Carbon Management Technology Consultation, Analysis and Cooperation Engage recognized experts in Fossil Energy and Carbon Management to provide advice and assistance to decision makers, stakeholders, state and local government officials, non-profit organizations, universities, non-governmental organizations, and the public as appropriate. These consultations could involve face-to-face meetings and discussions with the selected experts. Conduct analyses and prepare studies and reports on selected topics by Fossil Energy and Carbon Management experts to provide independent and unbiased perspectives on critical issues. These studies and reports would promote greater understanding of Carbon Management domestically and internationally. The information created will be used at seminars, conferences and workshops attended by various stakeholders, as well as disseminated domestically and internationally, as appropriate. Area 2: Carbon Management Technology Outreach Develop outreach materials that are custom tailored to be readily understood by domestic and international audiences so that its relevance is clear. These materials may include fact sheets, technical papers, flyers, briefing materials, displays, videos, and other products. In addition, information will be acquired from key Fossil Energy and Carbon Management-related activities and projects and added to a global outreach data base that can be used to target specific sectors of the public that may desire education on Carbon Management issues and developments. Area 3: Carbon Management Technology Technical Conference and Workshop Support Support efforts to increase the capacity of decision makers, stakeholders and the public to understand, develop and deploy Fossil Energy and Carbon Management Technologies. These programs will include conferences, workshops, fora or other events that benefit the public by providing insight and education. Organize and conduct technical workshops or seminars focused on specific Fossil Energy and Carbon Management-related topics (like identifying/eliminating key barriers to CDR deployment, assessing the impacts to Carbon Management of new/proposed policies or laws, etc.) and related issues each year in the U.S. These conferences should include speakers and participation by qualified, objective experts. As appropriate, summaries of the findings, outcomes, and/or discussions will be disseminated to the public. Support international Fossil Energy and Carbon Management-related conferences to exchange information in order to highlight developments, projects and deployment of Carbon Management in the U.S. and around the world. The audience would be domestic and international industry and government decision makers, technology developers, educators, policymakers, the public and other stakeholders. As appropriate, summaries of the findings, outcomes, and/or discussions will be provided to the public. Identify high level speakers from government and industry to convene on key technology, policy, regulatory and financial issues. Support U.S. efforts to participate in and assist the Carbon Management programs being pursued by organizations such as the World Energy Council (WEC), International Energy Agency (IEA) and the G-8 Energy Ministers. Program Area 2: Domestic and International Oil, Natural Gas, Methane Hydrates, Hydrogen, and Critical Minerals The DOEs Office of Fossil Energy and Carbon Managements Office of Resource Sustainability (ORS) administers the Departments technological development and approaches for reducing the environmental impacts of our historical and continued use of fossil fuels. Reducing the environmental impacts of fossil fuel infrastructure and reducing emissions throughout the supply chain is critical to achieving net-zero emissions. ORS supports a just transition to clean energy while minimizing the environmental impacts in sectors where fossil fuels are difficult to avoid. These goals are accomplished through policy, research, innovation, outreach, and stewardship. ORS advances technologies and solutions to reduce the environmental impacts and emissions associated with fossil energy development, use, transportation, and storage. This includes reducing emissions in the production, transportation, and storage of oil and natural gas; developing advanced remediation technologies for produced water, abandoned mines, abandoned wells, and the conversion of methane to useful products; and improving the economics and environmental performance of critical minerals extraction, processing, use, and disposal. ORS also regulates the import and export of natural gas, conducts analysis of fossil fuel and carbon markets, assesses policy and regulatory proposals, leads outreach for domestic and international engagements, and addresses environmental and energy justice impacts for communities most impacted by fossil fuel development and use. ORS areas of interest are described as follows. Areas of Interest Area 1: Oil, Natural Gas, Hydrogen, and Critical Minerals Consultation, Analysis, and Cooperation Engage recognized experts in global oil, natural gas, hydrogen, and critical minerals to provide advice and assistance to Government and private decision makers, U.S. industry representatives, non-governmental organization (NGO) leaders, and other members of the public who make critical decisions about global oil, natural gas, hydrogen and critical minerals policy. These consultations could involve face-to-face meetings and discussions with the selected global oil, natural gas, hydrogen, and critical minerals experts. Develop market analyses, technical studies, in-person and virtual workshops, and stakeholder events for policy level officials, industry leaders, NGOs, universities, non-profit organizations, and public figures. These events will provide independent and unbiased perspectives on topics associated with oil and natural gas and clean energy development such as mitigating environmental impacts, greenhouse gas (GHG)/methane emissions, natural gas markets and trade, petrochemicals, hydrogen production and transportation, critical minerals, and local and community impacts of energy projects. As appropriate, summaries of the findings, outcomes, and/or discussions from the events will be provided to the public. Support in-person and virtual workshops and events to promote DOE studies and papers on technical, regulatory, climate (e.g., carbon and methane management), environment, community, and/or economic issues related to oil, natural gas, hydrogen, and critical minerals for stakeholders in the US and other countries. Support ongoing Working (WG), Technical (TG), and Stakeholder (SG) Advisory Groups, including those of the Greenhouse Gas Supply Chain Emissions Measurement, Monitoring, Reporting and Verification (MMRV) Framework, through coordinating and implementing in-person or virtual meetings; recording meeting attendance; drafting and distributing meeting notes to include documenting and tracking recommendations and action items; assisting in developing PowerPoint summary materials for briefings; and establishing and maintaining international project coordination online portals for communication and disseminating and receiving information from the WG/TG/SGs; and coordinating information flow among the WG/TG/SGs. Area 2: Oil, Natural Gas, Methane Hydrates, Hydrogen, and Critical Minerals Bilateral and Regional Initiatives and Activities Assist in the organization and implementation of meetings, conferences, workshops, and task force related events on oil, natural gas, methane hydrates, hydrogen, and critical minerals technologies with global partners including foreign governments, companies, universities, and NGOs. These meetings, conferences, workshops, and task force events benefit the public by allowing officials in the U.S. Government and other governments, U.S. and foreign industry leaders, and NGO leaders to exchange information about advanced technologies and best practices in oil, natural gas, methane hydrates, hydrogen, and critical minerals development. Examples of such ORS events are the US India Low Emission Gas Task Force (LEGTF) under the US India Strategic Clean Energy Partnership (SCEP); Mozambique Initiative; and Greenhouse Gas Supply Chain Emissions Measurement, Monitoring, Reporting and Verification (MMRV) Framework. As appropriate, summaries of the findings, outcomes, and/or discussions from these events will be provided to the public, including through webpages. For the above-listed and similar initiatives and activities, identify and recruit appropriate public and private sector experts for speaking roles and for attendance. DOE may issue a FOA as described in the NOI; may issue a FOA that is significantly different than the FOA described in the NOI; or may not issue a FOA at all.

The "Precision Mental Health: Develop Tools to Inform Treatment Selection in Depression" grant aims to fund the development and early testing of predictive tools or biomarkers that can help determine the most effective treatment for individual patients suffering from depression.

With this solicitation, OJJDP seeks to support and strengthen collaborations between arts-based organizations and juvenile justice systems to develop, expand, or enhance promising and effective interventions that provide access to high-quality arts programs with and for current or previous justice-involved youth to reduce juvenile delinquency, recidivism, and/or other problem and high-risk behaviors. OJJDP defines justice-involved youth as those participating in court-ordered diversion programs in detention, correctional, or other residential facilities, and/or are on probation due to a delinquency finding by juvenile court.

This funding opportunity supports U.S. institutions in developing educational programs that provide undergraduate and early-stage graduate students with hands-on research experiences in kidney technology development and entrepreneurship.

The purpose of the program is to promote the delivery of health care services to rural underserved populations in the rural Northern Border Regional Commission (NBRC) service area of Maine, New Hampshire, New York, and Vermont. Through a consortia of local health care and social service providers, communities can develop innovative approaches to challenges related to specific health needs that expand clinical and service capacity. This program supports HRSA's collaboration with the Northern Border Regional Commission.

The Defense Advanced Research Projects Agency (DARPA) is soliciting innovative proposals in the following technical area: intravascular gas-exchange and trauma resuscitation through a single intravascular cannula. Proposed research should investigate innovative approaches that enable revolutionary advances which would develop the necessary device(s) to enable management of a polytrauma patient through a single intravascular access without the thrombotic complications associated with extracorporeal membrane oxygenation. Specifically excluded is research that primarily results in evolutionary improvements to the existing state of practice.

With this solicitation, OJP seeks to prevent and reduce violent crime in communities by supporting comprehensive, evidence-based community-based violence intervention and prevention programs. These programs include efforts to address gang and gun violence, based on partnerships among community residents, local government agencies, victim service providers, community-based organizations, law enforcement, hospitals, researchers, and other community stakeholders. OJP’s Bureau of Justice Assistance (BJA) is administering the opportunity, working in partnership with OJP’s Office of Juvenile Justice and Delinquency Prevention (OJJDP) and Office for Victims of Crime (OVC). This collaborative approach will help ensure jurisdictions have access to expertise to address community violence that involves youth, young adults, and adults, both as the individuals responsible for perpetrating this violence and as those who are victims of it. Awards made under this solicitation may be managed by BJA, OJJDP, or OVC, depending on the nature of the project.

Notice of Funding Opportunity Summary The Natural Resources Conservation Service (NRCS), an agency under the United States Department of Agriculture (USDA), is announcing the potential availability of funding for the purpose of leveraging NRCS resources to encourage collaboration with partners in conducting outreach and providing strategic conservation delivery assistance that enhances the ability of the agency to support conservation. The overall intent of this solicitation is to solicit partnerships to help enhance the implementation of key conservation objectives and priorities outlined in this announcement. Proposals will be accepted from eligible entities for outreach and technical assistance in Maine. NRCS anticipates the total amount awarded under this announcement in Federal fiscal year 2024 will be approximately $500,000. Proposals are requested from eligible entities for competitive consideration of agreement awards and projects between For new users of Grants.gov, see Section D. of the full Notice of Funding Opportunity for information about steps required before submitting an application via Grants.gov. Key Dates Applicants must submit their applications via Grants.gov by 11:59 pm Eastern Time on April 19, 2024. For technical issues with Grants.gov, contact Grants.gov Applicant Support at 1-800-518-4726 or support@grants.gov. Awarding agency staff cannot support applicants regarding Grants.gov accounts. For inquiries specific to the content of the NFO requirements, contact the federal awarding agency contact (section G of this NFO). Please limit questions to those regarding specific information contained in this NFO (such as dates, page numbers, clarification of discrepancies, etc.). Questions related to eligibility, or the merits of a specific proposal will not be addressed. The agency anticipates making selections by May 10, 2024 and expects to execute awards by September 6, 2024. These dates are estimates and are subject to change.

This funding opportunity supports exploratory preclinical studies to evaluate the effectiveness of therapeutic agents for rare diseases affecting fewer than 200,000 people in the U.S., aiming to advance these treatments toward clinical trials.

This Notice of Funding Opportunity (NOFO) invites grant applications from institutions/organizations that propose to build a Medical Rehabilitation Research Center. The centers will have a specific rehabilitation research theme and be comprised of a research project supported by 3 cores. The 3 cores will have functions within the center as well as functions nationwide. Together, the cores will support: administrative functions (including an optional pilot program), resource sharing, and community engagement and outreach. The Medical Rehabilitation Research Centers will contribute tomedical rehabilitation research infrastructure by developing and disseminating techniques, data, theories, research programs, and expertise with the goal of enhancing the capability of medical rehabilitation investigators to understand mechanisms of functional recovery, develop therapeutic strategies, identify clinical care gaps, and improve the lives of people with disabilities. Applications must include a plan for inclusion of People with Lived Experience (as a required other attachment) that is relevant to the research theme of the center and increases the potential impact of the center.

Department of the Interior - Bureau of Land Management Arizona (AZ) State Office Wildlife Program

Bureau of Land Management Arizona State Office Plant Conservation and Restoration Management Program

With this solicitation, NIJ seeks research partnership proposals that meet the needs and missions of local justice and service provider entities including police, corrections, courts, victim services, forensic science service providers, and community safety and adult and juvenile justice entities and the communities they serve. These partnerships should apply a data-driven, problem-solving approach to challenges prioritized by agency partners; identify actionable and measurable responses; implement changes; and employ an action research evaluation approach to assessing the impact of interventions on desired outcomes that emphasizes scientific rigor and meaningful stakeholder engagement. These partnerships should also focus on developing the entitys capacity to adopt data-driven, problem-solving approaches to sustain effective practices and ongoing improvement in relevant safety and justice outcomes.

This program funds projects that improve the safety, efficiency, and reliability of intercity passenger and freight rail. The Consolidated Rail Infrastructure and Safety Improvements (CRISI) Program is authorized under 49 U.S.C. 22907. The purpose of the CRISI Program is to invest in a wide range of projects within the United States to improve railroad safety, efficiency, and reliability; mitigate congestion at both intercity passenger rail and freight rail chokepoints to support more efficient travel and goods movement; enhance multi-modal connections; and lead to new or substantially improved Intercity Passenger Rail Transportation corridors. This program invests in railroad infrastructure projects that improve safety, support economic vitality (including through opportunities for small businesses), create good-paying jobs with the free and fair choice to join a union, increase capacity and supply chain resilience, apply innovative technology, and explicitly address climate change, gender equity and racial equity. The purpose of this notice is to solicit applications for the competitive CRISI Program provided in Consolidated Appropriations Act, 2023, division L, title I, Public Law 117–328 (2023 Appropriation), Consolidated Appropriations Act, 2024, division F, title I, Public Law 118–42 (2024 Appropriation) and the 2023 and 2024 advance appropriation in the Infrastructure Investment and Jobs Act, division J, title II, Public Law 117–58 (2021).

Department of the Interior - Bureau of Land Management Arizona Invasive and Noxious Plant Management

The Rural program is dedicated to enhancing surface transportation infrastructure within rural communities, with $780 million allocated for this purpose. It supports highway, bridge, and tunnel projects that improve freight, safety, and access to agricultural, commercial, energy, or transportation facilities critical to a rural area's economy. This program recognizes the unique challenges faced by smaller communities in accessing funding and aims to support projects that address these needs directly. The submission deadline is May 6, 2024.

This(NOFO) aims to innovate, implement, and evaluate approaches to One Health laboratory diagnostic network optimization and specimen transport in Liberia. This multi-component NOFO is designed to address the inter-dependence of a comprehensive, resource-mapped, accredited national and sub-national laboratory network, the physical transportation architecture required to transfer network commodities (namely human, animal, and environmental specimens) point-to-point, and the optimization of digital communication, information, and supply chain systems necessary to sustain the network itself.

The purpose of this notice of funding opportunity (NOFO) is to solicit applications to participate in the Immunobiology of Xenotransplantation Cooperative Research Program (IXCRP), a multi-center program dedicated to resolving immunologic and physiologic barriers to safe and efficacious xenotransplantation using preclinical pig to nonhuman primate (NHP) or human decedent models of pancreatic islet, kidney, heart, lung, or liver xenotransplantation. Transplantation is often the preferred or only therapy for end-stage organ disease. In 2023, 46,630 organ transplants were performed in the United States. In addition, transplantation of pancreatic islets offers a potential therapy for individuals with type 1 diabetes whose disease is not effectively managed with exogenous insulin. Unfortunately, with over 103,500 adults and children on the United Network for Organ Sharing (UNOS) waiting list, those in need of a transplant greatly exceed the number of available organs. It is estimated that 20 people on average die each day waiting for a transplant. Xenotransplantation offers a potential interim or definitive solution to the severe shortage of human organs and pancreatic islets. Pigs are the primary species of interest as xenograft donors due to their favorable reproductive capacity, and anatomical and physiological similarities to humans. However, there are multiple barriers to successful clinical xenotransplantation, including immunologic rejection of non-human organs and tissues by the human immune system, physiological differences between non-human and human molecules that prevent proper functioning of various biochemical pathways, and potential transmission of zoonoses. To address these challenges, the IXCRP was established by the National Institute of Allergy and Infectious Diseases (NIAID) in 2005 with a co-fund for type 1 diabetes from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (RFA-AI-04-042). Subsequently, in 2010, the program was renewed solely by NIAID (RFA-AI-09-035), in 2015 (RFA-AI-14-047 and RFA-AI-14-048), and in 2020 (RFA-AI-19-042 and RFA-AI-19-043). IXCRP investigators and other researchers in the field have made significant advances over the past two decades, and NIAID is committed to support this challenging area of research. Historically, the most significant hurdle to successful xenotransplantation was hyperacute rejection caused by preformed, xenoreactive naturally-occurring antibodies (XNA) that destroy the xenograft within hours post-transplant. The primary target of XNA is a carbohydrate epitope, galactose-alpha-(1,3)-galactose (Gal), which is not present in humans and Old World NHPs. To overcome this hurdle, two decades ago, the enzyme responsible for terminally linking Gal onto oligosaccharide chains, alpha-1,3 glycosyltransferase (GT), was knocked out in genetically modified pigs. Xenografts from GT knockout (GTKO) pigs elicit substantially less severe hyperacute rejection in NHPs. Cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) gene knockouts and mutations to beta-1,4-N-acetyl-galactosaminyltransferase 2 (B4GALNT2) were similarly engineered to reduce reactivity to other notable XNA to pig carbohydrate antigens, namely N-glycolylneuraminic acid-modified glycans and SDa swine blood group antigen, respectively. Over the last decade, application of CRISPR-Cas 9 technology combined with somatic cell nuclear transfer cloning has significantly accelerated the pace of multi-gene modification and donor pig production. Additional genetic modifications, most on the GTKO background, were developed to address key species-to-species incompatibilities and create more human-like organs. These include the insertion of human complement regulatory proteins to minimize the deleterious effects of the complement cascade in antibody-mediated rejection, human thrombomodulin and/or tissue factor pathway inhibitor to overcome coagulation pathway dysfunction, and human anti-inflammatory and/or immune suppressive genes to reduce immune activation contributing to graft rejection. These strategies have dramatically reduced the frequency and severity of hyperacute rejection and have prolonged survival in pig-to-NHP xenotransplantation models for up to 4 years. Success in prolonging xenograft survival in the pig-to-NHP model allows more in-depth investigation of the remaining immunologic and physiologic issues that must be addressed in order to achieve safe and efficacious clinical xenotransplantation. These include physiologic differences that influence xenograft function and long-term survival, and risks associated with zoonoses. Transmission of pathogenic zoonoses to a human recipient and, potentially, the general population is a concern. To reduce this risk, animals used for xenotransplantation are bred in specific-pathogen-free conditions, weaned early or caesarian-derived, and routinely screened to eliminate most, if not all, known zoonotic agents. Porcine Cytomegalovirus (PCMV) is a swine pathogen known to have deleterious effects on xenograft survival. In the first human patient to receive a cardiac xenotransplant, conventional testing failed to detect latent PCMV in the donor pig and the virus reactivated post-transplant. The extent to which PCMV reactivation contributed to the patient’s death is unknown; however, this event underscores the need for sensitive and reliable assays to detect both latent and active infection with PCMV. Porcine endogenous retroviruses (PERV), another potential zoonotic threat, were successfully inactivated in a line of pigs through a combination of CRISPR-Cas9 gene-editing and somatic cell nuclear transfer, further highlighting the potential of these technologies to both protect against immunologic attack and reduce the risk of zoonoses. The field of xenotransplantation has recently witnessed an expansion in research models beyond NHP recipients to include an evaluation of safety, feasibility, and short-term outcomes (2 – 60 days) in humans declared to have irreversible loss of brain function (individuals with brain death, also referred to as human decedents) maintained on cardiopulmonary support. These experiments, using varying genetically modified pig hearts and kidneys transplanted into human decedents whose organs were declined for allotransplantation based on organ quality, have demonstrated early hemodynamic stability, an absence of hyperacute rejection, and basic organ functionality under immunosuppression. No chimerism or transmission of porcine retroviruses were detected; however, many of these experiments have demonstrated thrombotic microangiopathy and/or antibody-mediated injury. As of the time of this writing, medical teams that include IXCRP-funded investigators have performed two pig-to-human orthotopic heart transplants under expanded access (compassionate use) authorization from the FDA. The two xenograft recipients expired at 8 and 6 weeks, respectively. These initial clinical xenotransplants demonstrated good early xenograft function but also highlighted fundamental gaps in our knowledge of 1) critical pathways leading to inflammation and graft failure, 2) best practices for zoonotic viral surveillance and treatment, 3) optimal design of the donor pig, and 4) postoperative immunosuppression regimen. These knowledge gaps must be addressed prior to broader clinical translation. Scope and Research Objectives The re-issue of the IXCRP will support research projects centered around preclinical NHP and/or human decedent models of porcine pancreatic islet, kidney, heart, lung, or liver xenotransplantation. The research objectives must address one or more of the remaining key immunologic and physiologic barriers to achieving safe and efficacious xenotransplantation, including issues affecting engraftment, survival, and function of xenografts. Research foci may include 1) development or optimization of the models themselves, including genetic modifications of the pig-donor to address FDA concerns, as well as refinement of surgical xenotransplantation techniques, 2) development or optimization of the immunosuppression (IS) regimen to prevent rejection and minimize toxicity, 3) characterization and resolution of physiological and immunological barriers to long-term xenograft survival, and 4) development or optimization of strategies to screen for and prevent pathogen transmission to recipients. Examples of research topics may include, but are not limited to the following: Elucidation of the cellular and molecular mechanisms of and development of strategies to prevent hyperacute, acute, and chronic xenograft rejection; Characterization of the recipient’s innate and adaptive immune responses to the xenograft; Evaluation of regimens to induce and maintain immune tolerance to xenografts and/or delineation of cellular and molecular mechanisms promoting xenograft tolerance; Development and characterization of strategies to prolong xenograft survival in life-supporting xenotransplantation models; Development of approaches to eliminate or minimize the use of immunosuppressive drugs through genetic modifications of donor organs/tissues/cells, utilization of encapsulation techniques, or other tolerogenic approaches; Characterization of and application of approaches to address differences in the anatomical, physiological, and/or endocrinological features of donor pig organs, tissues, or cells that limit a xenograft’s survival and function in NHP or human decedent recipients; Delineation and study of cross-match differences between pigs and NHPs or humans; Development and testing of tools/approaches to diagnose, monitor, and treat porcine zoonoses in human decedent models; Development and testing of tools/approaches to diagnose, monitor, and treat xenograft rejection; and Development and testing of tools/approaches to diagnose, monitor, and treat causes of xenograft dysfunction other than immunologic rejection. Applications proposing any of the following will be considered non-responsive and will not be reviewed: Pig-to-NHP xenotransplantation studies of any organs, tissues, or cells other than pancreatic islets, kidney, heart, lung, or liver. Small animal models of xenotransplantation, such as rodent models, unless the model is proposed only as an in vivo bioassay of large animal immune function (e.g., trans in vivo delayed type hypersensitivity assay); Clinical trials or clinical/human studies of xenotransplantation; (only preclinical human decedent model research is allowed). Studies of zoonotic agents or infections, except for those studies designed to prevent transmission of, or improve diagnosis, monitoring, or treatment of zoonotic infections in xenograft recipients. Studies focused on HIV/AIDS-related research. Applications that do not include annual milestones. Applications that propose studies in human decedents but do not include a Human Decedent Research Plan. Milestones The research plan must include explicit, detailed, and quantitative annual milestones. These milestones will be used by NIAID program staff to assess annual progress and support funding decisions. Steering Committee Program Directors/Principal Investigators (PD(s)/PI(s)) of awards funded under this program will form a Steering Committee after award. The Steering Committee will serve as the main governing body of the IXCRP. At annual meetings, the Steering Committee will review progress of xenotransplantation projects, provide guidance and recommendations to investigators regarding study implementation and conduct, identify scientific opportunities, emerging needs, and impediments to success, and encourage collaborations among consortium members. The voting members of the Steering Committee will include the PD/PI (contact PI) from each single project U01 award and the PD/PI (contact PI) plus one project leader from each multi-project U19 award. Additional PDs/PIs, Project Leaders, Core Leaders, and the NIH Project Scientist will serve as non-voting Steering Committee members. All IXCRP investigators will be required to accept and implement common guidelines and procedures approved by the Steering Committee. Applicants are encouraged to consider using the following NIAID-supported programs: The Immunology Database and Analysis Portal (ImmPort) The Immunology Database and Analysis Portal (ImmPort) program will provide support for public sharing of research data and experimental protocols of the IXCRP. ImmPort is a NIAID-funded data sharing platform, which has developed templates for data collection, standardization, and sharing from various NIAID-supported research programs. The IXCRP recipients are encouraged to participate with ImmPort in developing data standards for IXCRP-specific data types, where applicable, and be responsible for collecting and submitting data and documents into ImmPort. The IXCRP Steering Committee will provide information, consistent with the goals of the program and NIH policy, regarding research data and experimental protocol sharing within the IXCRP and with the public. The National Swine Resource and Research Center (NSRRC) The Office of Research Infrastructure Programs within the Division of Program Coordination, Planning, and Strategic Initiatives in the Office of the NIH Director supports the National Swine Resource and Research Center (NSRRC), which is co-sponsored by NIAID and the National Heart, Lung, and Blood Institute (NHLBI). The NSRRC was established in 2003 to develop the infrastructure needed to ensure that biomedical investigators across a variety of disciplines have access to critically needed swine models of human health and disease. The purpose of the NSRRC is to provide the biomedical research community enhanced access to critically needed swine models and to develop genetically modified swine when required for studies involving human health and diseases, including xenotransplantation. NIAID encourages IXCRP-funded investigators to submit relevant cell lines and animal models developed under this NOFO to the NSRRC, when applicable. This U01 NOFO is appropriate for applicants that are proposing a single research project while the companion U19 NOFO (RFA-AI-24-020) should be used for investigators proposing a more complex research program involving 2 or more research projects supported by cores. Applicants are strongly encouraged to discuss the proposed research with NIAID staff listed in the Scientific/Research contact well in advance of the application submission deadline. See Section VIII. Other Information for award authorities and regulations.

The purpose of this Notice of Funding Opportunity (NOFO) is to support milestone-driven projects focused on developing and utilizing novel predictive models, assays, tools, and/or platforms based on penetration and efflux of small molecules to facilitate therapeutic discovery for select Gram-negative bacterial pathogens: carbapenem-resistant Acinetobacter, carbapenem-resistant Enterobacteriaceae (CRE), and multidrug-resistant Pseudomonas aeruginosa. A number of Gram-negative bacterial pathogens are associated with the alarming increase in rates of drug resistance in healthcare and community settings. This group includes carbapenem-resistant Acinetobacter , carbapenem-resistant Enterobacterales (CRE), and MDR Pseudomonas aeruginosa that have been designated as “urgent” or “serious” threats in a recent report by the Centers for Disease Control and Prevention (CDC). A significant threat arises from the lack of effective therapeutic options available to treat some of these infections and is exacerbated by the scarcity of novel compounds effective against antimicrobial resistant (AR) and multidrug-resistant (MDR) Gram-negative bacteria in the discovery and development pipeline. In recent years, several public forums (including NIAID-sponsored workshops) identified the lack of understanding of the principles that govern compound penetration into, and efflux out of, Gram-negative bacteria as a key bottleneck for the rational discovery of novel lead therapeutic compounds. The paucity of suitable assays/tools/models to inform structure-activity relationships and guide optimization of whole cell penetration (and efflux avoidance) is reflected in the failure of medicinal chemistry efforts to advance novel chemical classes of compounds with Gram-negative activity. As more Gram-negative bacteria become resistant to antimicrobials and therapeutic options become limited or nonexistent, it becomes imperative to understand and rationalize the principles that allow molecules to penetrate Gram-negative bacteria, while avoiding efflux and overt toxicity toward eukaryotic cells. Therefore, developing new assays, tools, and models is paramount for overcoming this key bottleneck and facilitating the development of novel compounds targeting Gram-negative pathogens. Research Objectives and Scope The objective of this NOFO is to support milestone-driven projects focused on developing and utilizing novel predictive models, assays, tools, and/or platforms aimed at gaining a better understanding of the rules and compound properties that govern the penetration and efflux of drug-like small molecules into Gram-negative bacterial pathogens. This NOFO also supports the preclinical development of novel Gram-negative antibacterial therapeutics based on the tools and models hereby developed. Applications must focus on one or more of the following Gram-negative bacterial pathogens: carbapenem-resistant Acinetobacter, carbapenem-resistant Enterobacterales (CRE), and/or MDR Pseudomonas aeruginosa. Projects should complete assay/tool/model development prior to the end of the third year of the project period and initiate discovery activities to demonstrate its utility in supporting a corresponding medicinal chemistry program to generate a lead chemical series with demonstrated activity against one or more targeted Gram-negative bacteria. This NOFO will also support subsequent preclinical development of a promising lead antibacterial. Given the complex challenges of this research, this initiative encourages applications from multi-disciplinary teams composed of relevant experts in areas such as bacterial physiology, microbiology, bacterial membrane biology, medicinal chemistry, pharmacology, computation, and specialized technologies (microscopy, spectroscopy, electrophysiology, machine learning, etc.), as appropriate. Collaboration with, and utilization of, the NIAID Chemistry Center for Combating Antibiotic-Resistant Bacteria (CC4CARB), is recommended for completion of project relevant medicinal chemistry tasks. Close collaboration between academic and industry partners is highly encouraged to optimally combine innovative basic science with drug discovery expertise and proper access to compound libraries more typically available from industry. Examples of assay and model development activities include, but are not limited to: Quantitative cellular (or model system) assays to measure drug penetration and efflux, independent from standard minimum inhibitory concentration (MIC) testing; Innovative quantitative assays to measure drug concentrations in the bacterial cytoplasm and/or periplasmic space; Innovative technologies for dissecting and assessment of the kinetics of drug penetration and efflux from bacteria; and Computational algorithms for describing/predicting physical-chemical properties/guidelines needed by small molecules for optimal Gram-negative penetration and efflux avoidance. Applicants should demonstrate the utility of the developed tools and/or assays to predict and measure potency of candidate therapeutics against Gram-negative targets through one or more approaches. For example, using the developed models and/or assays to guide a medicinal chemistry campaign aimed at producing a novel chemical series with Gram-negative activity; screening existing libraries using the computational algorithms developed as a tool to find compounds with Gram-negative activity; or profiling existing libraries of compounds with known Gram-negative activity. Applications including the following will be considered non-responsive and will not be reviewed: Projects that do not focus on at least one select Gram-negative pathogen (carbapenem-resistant Acinetobacter, carbapenem-resistant Enterobacterales, or MDR Pseudomonas aeruginosa); Projects focused only on Gram-positive bacteria or Mycobacterium tuberculosis; Projects that do not focus on penetration and efflux of small molecules; Applications not containing a Milestone and Timeline attachment; Applications proposing Clinical trials; and Research on HIV/AIDS.

The purpose of this notice of funding opportunity (NOFO) is to solicit applications to participate in the Immunobiology of Xenotransplantation Cooperative Research Program (IXCRP), a multi-center program dedicated to resolving immunologic and physiologic barriers to safe and efficacious xenotransplantation using preclinical pig to nonhuman primate (NHP) or human decedent models of pancreatic islet, kidney, heart, lung, or liver xenotransplantation. Transplantation is often the preferred or only therapy for end-stage organ disease. In 2023, 46,630 organ transplants were performed in the United States. In addition, transplantation of pancreatic islets offers a potential therapy for individuals with type 1 diabetes whose disease is not effectively managed with exogenous insulin. Unfortunately, with over 103,500 adults and children on the United Network for Organ Sharing (UNOS) waiting list, those in need of a transplant greatly exceed the number of available organs. It is estimated that 20 people on average die each day waiting for a transplant. Xenotransplantation offers a potential interim or definitive solution to the severe shortage of human organs and pancreatic islets. Pigs are the primary species of interest as xenograft donors due to their favorable reproductive capacity and anatomical and physiological similarities to humans. However, there are multiple barriers to successful clinical xenotransplantation, including immunologic rejection of non-human organs and tissues by the human immune system, physiological differences between non-human and human molecules that prevent proper functioning of various biochemical pathways, and potential transmission of zoonoses. To address these challenges, the IXCRP was established by the National Institute of Allergy and Infectious Diseases (NIAID) in 2005 with a co-fund for type 1 diabetes from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (RFA-AI-04-042). Subsequently, in 2010, the program was renewed solely by NIAID (RFA-AI-09-035), in 2015 (RFA-AI-14-047 and RFA-AI-14-048), and in 2020 (RFA-AI-19-042 and RFA-AI-19-043).. IXCRP investigators and other researchers in the field have made significant advances over the past two decades, and NIAID is committed to support this challenging area of research. Historically, the most significant hurdle to successful xenotransplantation was hyperacute rejection caused by preformed, xenoreactive naturally-occurring antibodies (XNA) that destroy the xenograft within hours post-transplant. The primary target of XNA is a carbohydrate epitope, galactose-alpha-(1,3)-galactose (Gal), which is not present in humans and Old World NHPs. To overcome this hurdle, two decades ago, the enzyme responsible for terminally linking Gal onto oligosaccharide chains, alpha-1,3 glycosyltransferase (GT), was knocked out in genetically modified pigs. Xenografts from GT knockout (GTKO) pigs elicit substantially less severe hyperacute rejection in NHPs. Cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) gene knockouts and mutations to beta-1,4-N-acetyl-galactosaminyltransferase 2 (B4GALNT2) were similarly engineered to reduce reactivity to other notable XNA to pig carbohydrate antigens, namely N-glycolylneuraminic acid-modified glycans and SDa swine blood group antigen, respectively. Over the last decade, application of CRISPR-Cas 9 technology combined with somatic cell nuclear transfer cloning has significantly accelerated the pace of multi-gene modification and donor pig production. Additional genetic modifications, most on the GTKO background, were developed to address key species-to-species incompatibilities and create more human-like organs. These include the insertion of human complement regulatory proteins to minimize the deleterious effects of the complement cascade in antibody-mediated rejection, human thrombomodulin and/or tissue factor pathway inhibitor to overcome coagulation pathway dysfunction, and human anti-inflammatory and/or immune suppressive genes to reduce immune activation contributing to graft rejection. These strategies have dramatically reduced the frequency and severity of hyperacute rejection and have prolonged survival in pig-to-NHP xenotransplantation models for up to 4 years. Success in prolonging xenograft survival in the pig-to-NHP model allows more in-depth investigation of the remaining immunologic and physiologic issues that must be addressed in order to achieve safe and efficacious clinical xenotransplantation. These include physiologic differences that influence xenograft function and long-term survival, and risks associated with zoonoses. Transmission of pathogenic zoonoses to a human recipient and, potentially, the general population is a concern. To reduce this risk, animals used for xenotransplantation are bred in specific-pathogen-free conditions, weaned early or caesarian-derived, and routinely screened to eliminate most, if not all, known zoonotic agents. Porcine Cytomegalovirus (PCMV) is a swine pathogen known to have deleterious effects on xenograft survival. In the first human patient to receive a cardiac xenotransplant, conventional testing failed to detect latent PCMV in the donor pig and the virus reactivated post-transplant. The extent to which PCMV reactivation contributed to the patient’s death is unknown; however, this event underscores the need for sensitive and reliable assays to detect both latent and active infection with PCMV. Porcine endogenous retroviruses (PERV), another potential zoonotic threat, were successfully inactivated in a line of pigs through a combination of CRISPR-Cas9 gene-editing and somatic cell nuclear transfer, further highlighting the potential of these technologies to both protect against immunologic attack and reduce the risk of zoonoses. The field of xenotransplantation has recently witnessed an expansion in research models beyond NHP recipients to include an evaluation of safety, feasibility, and short-term outcomes (2 – 60 days) in humans declared to have irreversible loss of brain function (individuals with brain death, also referred to as human decedents) maintained on cardiopulmonary support. These experiments, using varying genetically modified pig hearts and kidneys transplanted into human decedents whose organs were declined for allotransplantation based on organ quality, have demonstrated early hemodynamic stability, an absence of hyperacute rejection, and basic organ functionality under immunosuppression. No chimerism or transmission of porcine retroviruses were detected; however, many of these experiments have demonstrated thrombotic microangiopathy and/or antibody-mediated injury. As of the time of this writing, medical teams that include IXCRP-funded investigators have performed two pig-to-human orthotopic heart transplants under expanded access (compassionate use) authorization from the FDA. The two xenograft recipients expired at 8 and 6 weeks, respectively. These initial clinical xenotransplants demonstrated good early xenograft function but also highlighted fundamental gaps in our knowledge of 1) critical pathways leading to inflammation and graft failure, 2) best practices for zoonotic viral surveillance and treatment, 3) optimal design of the donor pig, and 4) postoperative immunosuppression regimen. These knowledge gaps must be addressed prior to broader clinical translation. Scope and Research Objectives The re-issue of the IXCRP will support a research program comprised of two or more research projects centered around preclinical NHP and/or human decedent models of porcine pancreatic islet, kidney, heart, lung, or liver xenotransplantation. The research objectives must address one or more of the remaining key immunologic and physiologic barriers to achieving safe and efficacious xenotransplantation, including issues affecting engraftment, survival, and function of xenografts. Research foci may include 1) development or optimization of the models themselves, including genetic modifications of the pig-donor to address FDA concerns, as well as refinement of surgical xenotransplantation techniques, 2) development or optimization of the immunosuppression (IS) regimen to prevent rejection and minimize toxicity, 3) characterization and resolution of physiological and immunological barriers to long-term xenograft survival, and 4) development or optimization of strategies to screen for and prevent pathogen transmission to recipients. Examples of research topics may include, but are not limited to the following: Elucidation of the cellular and molecular mechanisms of and development of strategies to prevent hyperacute, acute, and chronic xenograft rejection; Characterization of the recipient’s innate and adaptive immune responses to the xenograft; Evaluation of regimens to induce and maintain immune tolerance to xenografts and/or delineation of cellular and molecular mechanisms promoting xenograft tolerance; Development and characterization of strategies to prolong xenograft survival in life-supporting xenotransplantation models; Development of approaches to eliminate or minimize the use of immunosuppressive drugs through genetic modifications of donor organs/tissues/cells, utilization of encapsulation techniques, or other tolerogenic approaches; Characterization of and application of approaches to address differences in the anatomical, physiological, and/or endocrinological features of donor pig organs, tissues, or cells that limit a xenograft’s survival and function in NHP or human decedent recipients; Delineation and study of cross-match differences between pigs and NHPs or humans; Development and testing of tools/approaches to diagnose, monitor, and treat porcine zoonoses in human decedent models; Development and testing of tools/approaches to diagnose, monitor, and treat xenograft rejection; and Development and testing of tools/approaches to diagnose, monitor, and treat causes of xenograft dysfunction other than immunologic rejection. Applications proposing any of the following will be considered non-responsive and will not be reviewed: Pig-to-NHP xenotransplantation studies of any organs, tissues, or cells other than pancreatic islets, kidney, heart, lung, or liver. Small animal models of xenotransplantation, such as rodent models, unless the model is proposed only as an in vivo bioassay of large animal immune function (e.g., trans in vivo delayed type hypersensitivity assay); Clinical trials or clinical/human studies of xenotransplantation; (only preclinical human decedent model research is allowed). Studies of zoonotic agents or infections, except for those studies designed to prevent transmission of, or improve diagnosis, monitoring, or treatment of zoonotic infections in xenograft recipients. Studies focused on HIV/AIDS-related research Applications that do not include annual milestones. Applications that propose studies in human decedents but do not include a Human Decedent Research Plan. Structure of the IXCRP Administrative Core: Each application will include an Administrative Core to manage and coordinate all activities to ensure project timelines and objectives are met. The Administrative Core will include a Program Management Plan that will guide its operations and activities. This Core will be responsible for carrying out activities described in the Data Management and Sharing Plan. The Administrative Core will also be responsible for organizing an annual programmatic meeting for all investigators and NIAID staff. Scientific Core: Scientific Cores are optional and may be included to provide IXCRP investigators with core resources and/or facilities that are essential for the activities of two or more Research Projects. Scientific Core activities must not overlap with each other or with the activities of a Research Project. The Scientific Core may not conduct research independent of the served Research Project. Research Projects: Applications will propose at least two synergistic Research Projects that meet the goals of the initiative to resolve the immunologic and physiologic barriers to safe and efficacious xenotransplantation using preclinical pig to nonhuman primate (NHP) or human decedent models of pancreatic islet, kidney, heart, lung, or liver xenotransplantation. Milestones The research projects must include explicit, detailed, and quantitative annual milestones. These milestones will be used by NIAID program staff to assess annual progress and support funding decisions. Steering Committee Program Directors/Principal Investigators (PD(s)/PI(s)) of awards funded under this program will form a Steering Committee after award. The Steering Committee will serve as the main governing body of the IXCRP. At annual meetings, the Steering Committee will review progress of xenotransplantation projects, provide guidance and recommendations to investigators regarding study implementation and conduct, identify scientific opportunities, emerging needs, and impediments to success, and encourage collaborations among consortium members. The voting members of the Steering Committee will include the PD/PI (contact PI) from each single project U01 award and the PD/PI (contact PI) plus one project leader from each multi-project U19 award. Additional PDs/PIs, Project Leaders, Core Leaders, and the NIH Project Scientist will serve as non-voting Steering Committee members. All IXCRP investigators will be required to accept and implement common guidelines and procedures approved by the Steering Committee. Applicants are encouraged to consider using the following NIAID-supported programs: The Immunology Database and Analysis Portal (ImmPort) The Immunology Database and Analysis Portal (ImmPort) program will provide support for public sharing of research data and experimental protocols of the IXCRP. ImmPort is a NIAID-funded data sharing platform, which has developed templates for data collection, standardization, and sharing from various NIAID-supported research programs. The IXCRP recipients are encouraged to participate with ImmPort in developing data standards for IXCRP-specific data types, where applicable, and be responsible for collecting and submitting data and documents into ImmPort. The IXCRP Steering Committee will provide information, consistent with the goals of the program and NIH policy, regarding research data and experimental protocol sharing within the IXCRP and with the public. The National Swine Resource and Research Center (NSRRC) The Office of Research Infrastructure Programs within the Division of Program Coordination, Planning, and Strategic Initiatives in the Office of the NIH Director supports the National Swine Resource and Research Center (NSRRC), which is co-sponsored by NIAID and the National Heart, Lung, and Blood Institute (NHLBI). The NSRRC was established in 2003 to develop the infrastructure needed to ensure that biomedical investigators across a variety of disciplines have access to critically needed swine models of human health and disease. The purpose of the NSRRC is to provide the biomedical research community enhanced access to critically needed swine models and to develop genetically modified swine when required for studies involving human health and diseases, including xenotransplantation. NIAID encourages IXCRP-funded investigators to submit relevant cell lines and animal models developed under this NOFO to the NSRRC, when applicable. The current U19 NOFO is appropriate for investigators proposing a complex research program involving 2 or more research projects supported cores while the companion U01 NOFO (RFA-AI-24-019) should be used for applicants that are proposing a single research project. Applicants are strongly encouraged to discuss the proposed research with NIAID staff listed in the Scientific/Research contact well in advance of the application submission deadline. See Section VIII. Other Information for award authorities and regulations.