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This Funding Opportunity Announcement (FOA) is intended to address the problem of misidentified cell lines. Many advances in biomedical science have arisen from studies of cultured cell lines, which are widely used for basic research on cell function, as models for disease, and for drug screening.  In most of this research, correct identification of the cell lines used is necessary to replicate experiments.  In addition, in a majority of the projects the cell lines used were chosen because they are predicated to recapitulate biologically important features of the tissue and/or tumor of origin, for example, driver mutations, expression patterns, and functional correlates of the differentiated state of the original tissue. Cell line origins are documented by chain of custody (a continuous chronological record documenting their source, transfer, analysis, and disposition).  However, cell lines in culture are prone to contamination by foreign cells, which may rapidly displace the original cells.  The identity of cultured cells should be routinely verified, but a majority of laboratories do not monitor the identity of their cell lines, and many cell lines are misidentified.  Analyses of cells submitted to major repositories such as the ATCC (American Type Culture Collection) and the DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen) have found that 15-40% of cell lines submitted by investigators are misidentified, i.e., they have a tissue or species of origin that differs from the one reported.  Similar frequencies of misidentification have been reported by research laboratories that have examined cell line collections.

A primary focus of these programs is on the use of in vitro methods and assays using lower organisms to screen thousands of chemicals for toxicity in order to identify mechanisms of compound-induced biological activity, characterize toxicity pathways, facilitate cross-species extrapolation, and provide input to models for low-dose extrapolation.  Data generated by these methods will be used to prioritize compounds for more extensive toxicological evaluation and to develop predictive models for biological response in humans. Current approaches are limited in terms of incorporating genetic variability in toxicity testing and in assessing the effects of chemicals in multiple normal tissue and cell types, relying on immortalized cell lines or primary cell lines derived from tissues. Thus, there is a need for novel, medium- to high-throughput assays (at least a 96-well format) to evaluate the effects of chemical compounds on the differentiation of pluripotent or multi-potent stem cells as well as the effects of chemical exposures on differentiated cell types representative of various in vivo tissues. Approaches can include the use of human induced pluripotent stem (iPS) cells, approved human embryonic stem (ES) cell lines, or ES or iPS cells derived from genetically characterized mouse strains. Assays should be able to measure the effects of toxicants on the differentiation process and/or on the differentiated cells themselves; cell types of high priority include but are not limited to cardiomyocytes, neural cells, hepatocytes, endothelial cells, lung (airway or alveolar) cells, and hormonally-responsive tissues such as reproductive tissues or breast epithelial cells.

In recent years, somatic cells as therapeutic agents have provided new treatment approaches for a number of pathological conditions that were deemed untreatable, or difficult to treat. Several successful cell therapies using T cells have been demonstrated for cancer and autoimmune diseases, while stem cell therapies have given relief for heart disease and stroke. Hundreds of clinical trials are ongoing to examine efficacy of cell therapies for a variety of other diseases including diabetes, Alzheimer's, Parkinson's, and Crohn's disease. Production of therapeutic cells is currently expensive and, therefore, cost prohibitive for the large number of people who might benefit from these treatments. The overarching goal of this Advanced Biomanufacturing of Therapeutic Cells (ABTC) solicitation is to catalyze well-integrated interdisciplinary research to understand, design, and control cell manufacturing systems and processes that will enable reproducible, cost-effective, and high-quality production of cells with predictable performance for the identified therapeutic function.

In recent years, somatic cells as therapeutic agents have provided new treatment approaches for a number of pathological conditions that were deemed untreatable, or difficult to treat. Several successful cell therapies using T cells have been demonstrated for cancer and autoimmune diseases, while stem cell therapies have given relief for heart disease and stroke. Hundreds of clinical trials are ongoing to examine efficacy of cell therapies for a variety of other diseases including diabetes, Alzheimer's, Parkinson's, and Crohn's disease. Production of therapeutic cells is currently expensive and, therefore, cost prohibitive for the large number of people who might benefit from these treatments. The overarching goal of this Advanced Biomanufacturing of Therapeutic Cells (ABTC) solicitation is to catalyze well-integrated interdisciplinary research to understand, design, and control cell manufacturing systems and processes that will enable reproducible, cost-effective, and high-quality production of cells with predictable performance for the identified therapeutic function.

The purpose of this funding opportunity announcement (FOA) is to stimulate research in the interplay between cell death pathways in nave and drug resistant cancers. Regulated cell death, especially apoptosis and necroptosis, are natural barriers that restrict malignant cells from surviving and disseminating. Evasion of cell death mechanisms is one of the hallmarks of cancer contributing to tumor progression, metastases and resistance to therapy. Recent studies show that the machinery to activate different forms of cell death coexists in cells but the crosstalk of cell death pathways in cancer has not been systematically studied. Research into the intersection of cell death programs will allow for better defining markers of cell death pathway at the molecular level and offers the possibility that the specific mediators of cell survival may be inhibited and/or the mediators of cell death enhanced, driving nave and drug resistant cancer cells toward effective cell death.

The purpose of this funding opportunity announcement (FOA) is to stimulate research in the interplay between cell death pathways in nave and drug resistant cancers. Regulated cell death, especially apoptosis and necroptosis, are natural barriers that restrict malignant cells from surviving and disseminating. Evasion of cell death mechanisms is one of the hallmarks of cancer contributing to tumor progression, metastases and resistance to therapy. Recent studies show that the machinery to activate different forms of cell death coexists in cells but the crosstalk of cell death pathways in cancer has not been systematically studied. Research into the intersection of cell death programs will allow for better defining markers of cell death pathway at the molecular level and offers the possibility that the specific mediators of cell survival may be inhibited and/or the mediators of cell death enhanced, driving nave and drug resistant cancer cells toward effective cell death.

Stem cell technology holds the promise of providing a nearly limitless source of safe, immune-matched cells for clinical use. One of the first areas where this promise can be realized is through cell products that lack a nucleus and thus face fewer regulatory hurdles, such as red blood cells and platelets. Considerable progress has been made but scientific questions remain and improved tools to enhance the production are required if translation to clinical use is to be achieved. To this end, this FOA will support research addressing remaining scientific questions to enable and accelerate the use of stem cell-derived blood products as therapeutics. While production of sufficient numbers of cells such as platelets and red cells has been demonstrated using cellular engineering methods, basic research questions related to cell differentiation and maturation remain, which if elucidated, may allow for the development of new ways to efficiently produce clinically-useful stem cell-derived platelets or red blood cells. In addition to this FOA, two companion FOAs (RFA-HL-15-029 and RFA-HL-15-030) will support small business research to develop improved techniques and tools to enhance the production of clinically-relevant, functional stem cell-derived red blood cells or platelets in a more efficient and cost-effective manner.

The National Science Foundation (NSF) Division of Chemical, Bioengineering, Environmental and Transport Systems (CBET), seeks proposals that elucidate mechanisms of, and develop strategies to, direct the differentiation of undifferentiated cells into mature, functional cells or organoids. Projects responsive to this solicitation must aim to establish a robust and reproducible set of differentiation design rules, predictive models, real-time sensing, control, and quality assurance methods, and integrate them into a workable differentiation strategy. They must develop a fundamental understanding of how cells develop, including mechanisms, molecular machinery, dynamics, and cell-cell interactions, and use this understanding to manipulate cells purposefully. Investigators can choose any undifferentiated cell type, from any animal species, as a starting point and choose any appropriate functional product (cell, organoid, etc.) with real-world relevance. This solicitation parallels NSF's investment in Understanding the Rules of Life (URoL): Predicting Phenotype, NSF's Big Idea focused on predicting the set of observable characteristics (phenotype) of an organism based on its genetic makeup and the nature of its environment and applies it to understanding and accomplishing the intentional and guided differentiation of an undifferentiated cell into cells, organoids or tissues with predetermined activities and functions.

The National Science Foundation (NSF) Division of Chemical, Bioengineering, Environmental and Transport Systems (CBET), seeks proposals that elucidate mechanisms of, and develop strategies to, direct the differentiation of undifferentiated cells into mature, functional cells or organoids. Projects responsive to this solicitation must aim to establish a robust and reproducible set of differentiation design rules, predictive models, real-time sensing, control, and quality assurance methods, and integrate them into a workable differentiation strategy. They must develop a fundamental understanding of how cells develop, including mechanisms, molecular machinery, dynamics, and cell-cell interactions, and use this understanding to manipulate cells purposefully. Investigators can choose any undifferentiated cell type, from any animal species, as a starting point and choose any appropriate functional product (cell, organoid, etc.) with real-world relevance.This solicitation parallels NSF's investment inUnderstanding the Rules of Life (URoL): Predicting Phenotype, NSF's Big Idea focused on predicting the set of observable characteristics (phenotype) of an organism based on its genetic makeup and the nature of its environment and applies it to understanding and accomplishing the intentional and guided differentiation of an undifferentiated cell into cells, organoids or tissues with predetermined activities and functions.

This Funding Opportunity Announcement (FOA) intends to support a Brain Cell Data Center (BCDC) that will work with other BICCN Centers and interested researchers to establish a web-accessible information system to capture, store, analyze, curate, and display all data and metadata on brain cell types, and their connectivity. The BCDC is expected to: (1) lead the effort to establish spatial and semantic standards for managing heterogeneous brain cell census data types and information; (2) lead the effort to collect and register multimodal brain cell census data to common brain coordinate systems; (3) generate searchable 2D and 3D digital brain atlases for cell census data; and (4) generate a unified and comprehensive brain cell knowledge base that integrates all existing brain cell census data and information across diverse repositories.  A central goal of this and the three companion FOAs is to build a brain cell census resource that can be widely used throughout the research community.

This Funding Opportunity Announcement (FOA) intends to accelerate the integration and use of scalable technologies and tools to enhance and reinvigorate brain cell census research, including the development of technology platforms and/or resources that will enable a swift and comprehensive survey of brain cell types and circuits. Of particular interest are those that will (a) improve technology and resource platforms to remove limitations and bottlenecks in the current pipeline of brain cell census data generation; (b) integrate experimental and computational methods to enhance capabilities of cell census data generation and analysis and to reduce barriers to hypothesis-driven research; (c) generate a substantial amount of spatiotemporal cell census data and/or resources to demonstrate the utility of the improved technology and resource platforms; and (d) conduct comparative studies by using proper criteria to evaluate and benchmark quality of biospecimen, performance of cell census tools/technologies, and effectiveness of computational approaches. The projects funded under this FOA will align with the overarching goals of the BRAIN Initiative Cell Census Network (BICCN) and are expected to generate a substantial amount of cell census data using the proposed technologies or via collaboration with the BICCN.

This funding opportunity announcement, in support of the NIH Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative aims to pilot classification strategies to generate a systematic inventory/cell census of cell types in the brain. Pilot projects are sought that would 1) provide cell census data in the whole brain, a brain region, or a significant functional circuit in the vertebrate nervous system; 2) integrate molecular identity of cell types with connectivity, morphology, and location; 3) apply statistical methods for creating a taxonomy of cell types based on molecular identity and connectivity; 4) provide realistic estimates on the number/percentage of defined cell types in specific region(s) and/or circuit(s); and 5) provide a basis to map cell types based on molecular identity and connectivity onto a reference brain atlas. These pilot projects and methodologies should be designed to demonstrate their utility and scalability to ultimately complete a comprehensive cell census of the human brain in the future.

The mission of the Biomedical Engineering (BME) program is to provide opportunities to develop novel ideas into discovery-level and transformative projects that integrate engineering and life science principles in solving biomedical problems that serve humanity in the long-term.  The Biomedical Engineering (BME) program supports fundamental research in the following BME themes: Neural engineering (brain science, computational neuroscience, brain-computer interface, neurotech, cognitive engineering) Cellular biomechanics (motion, deformation, and forces in biological systems; how mechanical forces alter cell growth, differentiation, movement, signal transduction, transport, cell adhesion, cell cytoskeleton dynamics, cell-cell and cell-ECM interactions; genetically engineered stem cell differentiation with long-term impact in tissue repair and regenerative medicine) The BME projects must be at the interface of engineering and life sciences, and advance both engineering and life sciences.  The projects should focus on high impact transforming methods and technologies. The project should include methods, models and tools of understanding and controlling of living systems; fundamental improvements in deriving information from cells, tissues, organs, and organ systems; new approaches to the design of structures and materials for eventual medical use in the long-term; and new novel methods of reducing health care costs through new technologies. The projects should emphasize the advancement of fundamental engineering knowledge, possibly leading to the development of new methods and technologies in the long-term; and highlight multi-disciplinary nature, integrating engineering and the sciences. The long-term impact of the projects can be related to disease diagnosis and/or treatment, improved health care delivery, or product development.

The mission of the Biomedical Engineering (BME) program is to provide opportunities to develop novel ideas into discovery-level and transformative projects that integrate engineering and life science principles in solving biomedical problems that serve humanity in the long-term.  The Biomedical Engineering (BME) program supports fundamental research in the following BME themes: Neural engineering (brain science, computational neuroscience, brain-computer interface, neurotech, cognitive engineering) Cellular biomechanics (motion, deformation, and forces in biological systems; how mechanical forces alter cell growth, differentiation, movement, signal transduction, transport, cell adhesion, cell cytoskeleton dynamics, cell-cell and cell-ECM interactions; genetically engineered stem cell differentiation with long-term impact in tissue repair and regenerative medicine) The BME projects must be at the interface of engineering and life sciences, and advance both engineering and life sciences.  The projects should focus on high impact transforming methods and technologies. The project should include methods, models and tools of understanding and controlling of living systems; fundamental improvements in deriving information from cells, tissues, organs, and organ systems; new approaches to the design of structures and materials for eventual medical use in the long-term; and new novel methods of reducing health care costs through new technologies.

This FOA encourages Research Project Grant (R01) applications from institutions and organizations proposing research aimed at characterizing animal stem cells and improving existing, and creating new, animal models for human disease conditions.The intent of this initiative is to facilitate the use of stem cell-based therapies for regenerative medicine. The initiative focuses on the following areas: 1) comparative analysis of animal and human stem cells to provide information for selection of the most predictive and informative model systems; 2) development of new technologies for stem cell characterization and transplantation; and 3) improvement of animal disease models for stem cell-based therapeutic applications.

This FOA encourages Research Project Grant (R01) applications from institutions and organizations proposing research aimed at characterizing animal stem cells and improving existing, and creating new, animal models for human disease conditions.The intent of this initiative is to facilitate the use of stem cell-based therapies for regenerative medicine. The initiative focuses on the following areas: 1) comparative analysis of animal and human stem cells to provide information for selection of the most predictive and informative model systems; 2) development of new technologies for stem cell characterization and transplantation; and 3) improvement of animal disease models for stem cell-based therapeutic applications.

This Funding Opportunity Announcement (FOA) invites cooperative agreement applications that will contribute to a higher resolution understanding of the physical and functional organization of the human islet tissue environment by describing the composition (cellular and molecular) and function of important components of the pancreatic islet and peri-islet tissue architecture, the cell-cell relationships and means of communications used by cell types and cell subtypes within the pancreatic tissue ecosystem, and/or the contribution of adjacent (including acinar, ductal, lymphatic) and neighboring (intestinal, mesenteric and adipose) tissues to islet cell function and dysfunction. Successful projects will integrate the Human Pancreas Analysis Consortium (HPAC), that will consist of the research teams funded in response to this FOA with the Human Pancreas Analysis Program (HPAP), a resource-generation program that was funded in 2016 in response to RFA-DK-15-027. HPAC will become the fifth consortium of the Human Islet Research Network (HIRN, https://hirnetwork.org/ ). HIRN's overall mission is to support innovative and collaborative translational research to understand how human beta cells are lost in T1D, and to find innovative strategies to protect and replace functional beta cell mass in humans. This FOA will only support studies with a primary focus on increasing our understanding of human tissue structure and function, and human disease biology (as opposed to rodent or other animal models). This FOA is not intended to support the conduct of a clinical trial.

This Funding Opportunity Announcement (FOA) invites cooperative agreement applications that will contribute to a higher resolution understanding of the physical and functional organization of the human islet tissue environment by describing the composition (cellular and molecular) and function of important components of the pancreatic islet and peri-islet tissue architecture, the cell-cell relationships and means of communications used by cell types and cell subtypes within the pancreatic tissue ecosystem, and/or the contribution of adjacent (including acinar, ductal, lymphatic) and neighboring (intestinal, mesenteric and adipose) tissues to islet cell function and dysfunction. Successful projects will integrate the Human Pancreas Analysis Consortium (HPAC), that will consist of the research teams funded in response to this FOA with the Human Pancreas Analysis Program (HPAP), a resource-generation program that was funded in 2016 in response to RFA-DK-15-027. HPAC will become the fifth consortium of the Human Islet Research Network (HIRN, https://hirnetwork.org/ ). HIRN's overall mission is to support innovative and collaborative translational research to understand how human beta cells are lost in T1D, and to find innovative strategies to protect and replace functional beta cell mass in humans. This FOA will only support studies with a primary focus on increasing our understanding of human tissue structure and function, and human disease biology (as opposed to rodent or other animal models). This FOA will not accept applications proposing a clinical trial.

The purpose of this Funding Opportunity Announcement (FOA) is to encourage applications from the scientific community to support outstanding research in the area of spermatogenic stem cell (SSC) biology.The overarching goal is to increase the chances that couples may have biological offspring without using conventional assisted reproductive modalities (i.e., IVF, ICSI).A focal point of the initiative is on the development of new techniques to culture and expand these cells over an extended period of time.Another area of study includes methods to eliminate malignant cells from SSC cultures following chemotherapy/radiation treatment. Also, spermatogenic stem cells from human adults could have a major impact on drug development and toxicity testing as animal-based systems do not sufficiently mirror the situation in humans.

The purpose of this Funding Opportunity Announcement (FOA) is to encourage applications from the scientific community to support outstanding research in the area of spermatogenic stem cell (SSC) biology.The overarching goal is to increase the chances that couples may have biological offspring without using conventional assisted reproductive modalities (i.e., IVF, ICSI).A focal point of the initiative is on the development of new techniques to culture and expand these cells over an extended period of time.Another area of study includes methods to eliminate malignant cells from SSC cultures following chemotherapy/radiation treatment. Also, spermatogenic stem cells from human adults could have a major impact on drug development and toxicity testing as animal-based systems do not sufficiently mirror the situation in humans.

One of JDRF's therapeutic goals is to restore beta cell function in type 1 diabetes (T1D) by replacement/transplantation of beta cells/islets. Pancreatic islet transplantation has been efficacious in selected patients in improving metabolic control and quality of life, and in preventing severe hypoglycemia in patients with medically unstable T1D. Despite improvements in cadaveric pancreas procurement, islet isolation, and islet purification, major scientific and technical challenges remain that must be addressed before beta cell replacement could be widely incorporated into the clinical management of established T1D; examples include serious side effects from chronic immunosuppression and the insufficient human islet supply from cadaveric pancreata. JDRF's role is to enable the scientific community to address these challenges with the ultimate goal of developing safe and effective beta cell replacement approaches available to large numbers of individuals with T1D.

One of JDRF's therapeutic goals is to restore beta cell function in type 1 diabetes (T1D) by replacement/transplantation of beta cells/islets. Pancreatic islet transplantation has been efficacious in selected patients in improving metabolic control and quality of life, and in preventing severe hypoglycemia in patients with medically unstable T1D. Despite improvements in cadaveric pancreas procurement, islet isolation, and islet purification, major scientific and technical challenges remain that must be addressed before beta cell replacement could be widely incorporated into the clinical management of established T1D; examples include serious side effects from chronic immunosuppression and the insufficient human islet supply from cadaveric pancreata. JDRF's role is to enable the scientific community to address these challenges with the ultimate goal of developing safe and effective beta cell replacement approaches available to large numbers of individuals with T1D.

The purpose of this FOA is to support generation of single cell RNA-sequencing datasets for at least one brain region relevant to persistent HIV infection and opioid use disorder. Applications that are not responsive to this FOA will be returned without review. To be responsive to this FOA, proposed projects should be framed to answer one or more vexing questions about persistent HIV infection in the CNS. The major thrust of the proposed project also MUST: exploit single nucleus or single cell transcriptomic assays with the goal of identifying the types of cells within at least one NIDA-relevant brain region (e.g. PFC, NAc, VTA, striatum, insula, or other appropriately justified region) and how the cell types and individual cells within that region differ from one another in terms of gene expression. focus on human post-mortem brain tissue from controls, individuals with chronic opioid exposure, HIV-infected individuals, and HIV-infected individuals with chronic opioid exposure. propose to detect HIV proteins or RNA or DNA within the single cells or nuclei to be assayed.

This Funding Opportunity Announcement (FOA) requests applications to explore human pancreatic tissues for the discovery of early biomarkers of T1D pathogenesis, the description of specific signaling or processing pathways that may contribute to the asymptomatic phase of T1D, the development of clinical diagnostic tools for the detection and staging of early T1D in at-risk or recently-diagnosed individuals, and/or the identification of therapeutic targets for the development of preventative or early treatment strategies. Successful applicants will join the Consortium on Beta Cell Death and Survival (CBDS), whose mission is to better define and detect the mechanisms of beta cell stress and destruction central to the development of T1D in humans, with the long-term goal of detecting beta cell destruction and protecting the residual beta cell mass in T1D patients as early as possible in the disease process, and of preventing the progression to autoimmunity. The CBDS is part of a collaborative research framework, the Human Islet Research Network (HIRN, https://hirnetwork.org), whose overall mission is to support innovative and collaborative translational research to understand how human beta cells are lost in T1D, and to find innovative strategies to protect and replace functional beta cell mass in humans. This FOA will only support studies with a primary focus on increasing our understanding of human disease biology (as opposed to rodent or other animal models).