Grants for Independent School Districts

**A modification to this NOFO was made on April 4, 2024. There are no content changes to application or program requirements. The funding opportunity number was changed from HHS-2024-ACF-ACYF-CW-0056 to HHS-2024-ACF-ACYF-CT-0056. There were changes made in Section I, Statutory Authority; and Section II, Expected Number of Awards and Estimated Total Funding. In Section III, Eligibility was changed to exclude for-profit organizations and small businesses. American Indian and Alaska Native (AI/AN) children are nearly 3 times more likely to enter foster care, compared to non-Native children. These four year grants are intended to generate evidence for how best to effectively implement child welfare practices and ongoing active efforts to maintain AI/AN families by funding state and tribal partnerships to jointly design and operate Indian child welfare best practice implementation demonstration sites. The evidence generated and lessons learned through this effort are intended to contribute to implementation efforts nationally to help maintain and preserve AI/AN families and allow their children to remain connected to their communities and cultures. The purpose of this notice of funding opportunity is to create and implement intergovernmental partnership models to improve implementation of child welfare best practices that are culturally appropriate for federally recognized AI/AN children to prevent maltreatment, removal from families and communities, and improve safety, permanency, and well-being. Recipients will serve as demonstration sites to design and implement projects to effectively implement culturally appropriate best practices in Indian child welfare, including measuring improvements in child welfare practice, Indian child welfare codes, legal and judicial processes, case monitoring, case planning, data collection, in-home family preservation services, infrastructure, and systems change. Partnerships must include the state Court Improvement Program, the state child welfare agency, and one or more tribal governments or tribal consortia including corresponding tribal court(s). The "Tribal government" partner(s) may be tribal child welfare agencies where appropriate under tribal law or custom.Effective culturally appropriate best practices for implementation require a high degree of collaboration between state and tribal courts and Indian child welfare agencies. Thus, both states and tribes must identify, build, and enhance necessary capacities. State/tribal collaborations will work together to craft solutions for longstanding challenges to providing effective best practices in Indian child welfare in ways that work best for their communities. This funding opportunity is intended to encourage state and tribal governments to work together to find creative, rational ways to meet the needs of AI/AN families with culturally appropriate best practices in Indian child welfare, with active efforts to retain or reunite Indian children with family as the gold standard for best Indian child welfare practice. The award also provides an important opportunity for states and tribes to build or strengthen relationships of trust by working together toward common family preservation goals. As part of the project, recipients may also consider the role of civil legal services in implementation efforts. Assessment of the success and/or need for legal representation to parties in Indian child welfare cases may be included in project work, as may provision of direct civil legal services, to the extent that such legal services are an identified part of a pilot or practice model to be tested.For purposes of this funding opportunity, "Tribal courts" are defined consistent with the Bureau of Indian Affairs regulations as "a court with jurisdiction over child custody proceedings and which is either a Court of Indian Offenses, a court established and operated under the code or custom of an Indian tribe, or any other administrative body of a tribe which is vested with authority over child custody proceedings.

Synopsis: NOFO # DD24-0051 solicits non-research, cooperative agreement applications to conduct population-based surveillance of congenital heart defects (CHD) to describe health outcomes including health equity, with the goal of identifying opportunities to improve the health of all people living with CHD. This project will involve a required component (A) and an optional component (B). The population included in this surveillance activity can be an entire state or a region within a state. Individuals with CHD should be identified through existing data sources including the jurisdiction birth defects surveillance system, electronic health records, administrative data (e.g., Medicaid/Medicare, hospital discharge), or other sources available to funding recipients. Background: Congenital heart defects (CHD) affect about 1% of all births in the United States, and are a leading cause of birth defect-associated infant mortality, morbidity, and healthcare costs. Improvements in early detection and treatment of CHD and consequently in survival have resulted in many people, including those affected by a severe CHD, living into adolescence and adulthood. An estimated two million persons in the U.S. are living with a CHD, including over one million adults; about 12% of these affected adults have a severe CHD. Most current efforts to conduct population-based surveillance of CHD have focused on monitoring newborns. However, little data exist on the descriptive epidemiology of CHD beyond early childhood in the U.S. Despite the public health burden, the lack of population-based surveillance precludes reliable data on people with CHD, their survival, healthcare utilization, and characteristics associated with long-term outcomes. Through this surveillance activity, these data will be assessed, enabling and informing efforts to improve the health and well-being of people with CHD. Objectives: Component A objectives include: (1) assess survival, comorbidities, healthcare utilization during the period 2021-2023, and characteristics associated with long-term outcomes among people with CHD; (2) assess health equity among people with CHD; (3) examine state and national healthcare policies that have an impact on people with CHD; (4) examine COVID-19 and related data such as health care utilization during the pandemic among people with CHD; and (5) work with local/state partners to use site-specific CHD data. Component B objectives include: (1) develop and refine a machine learning algorithm for the surveillance data collected through Component A; and (2) apply this machine learning algorithm to data collected from all recipients funded through Component A.

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 providing strategic conservation delivery assistance and/or provide tools or data that enhance the ability of the agency to support conservation activities. 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 projects located in New Jersey. NRCS anticipates the total amount awarded under this announcement in Federal fiscal year 2024 will be up to $75,000.00 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 June 7th, 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.

With this solicitation, NIJ seeks applications for funding of rigorous, independent evaluation projects funded under the OJP Community-Based Violence Intervention and Prevention Initiative (CVIPI). This solicitation includes two funding categories: 1) Evaluation research of programmatic sites funded under the OJP FY23 and FY24 CVIPI solicitations; and 2) evaluation research of other community-violence programs.

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.

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.

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.

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

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.

The Effectiveness Monitoring Committee (EMC), serving as an advisory body to the Board of Forestry and Fire Protection, aims to fund scientific research that tests the effectiveness of the California Forest Practice Rules and associated regulations. This includes addressing natural resource issues such as watershed science, wildlife concerns, and wildfire hazard. Proposals are sought that focus on one or more of EMC's Research Themes and Critical Monitoring Questions, particularly those that contribute to understanding and enhancing wildfire resilience and response to climate change across California's forestlands. Projects must directly relate to management activities on private timberlands in the state, although those on public lands may qualify if they demonstrate relevance to non-federal timberland activities.