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NEI - National Eye Institute

Project Summary Retinal ganglion cells (RGCs) send visual information from the retina to the brain via the optic nerve. Their degeneration underlies several major eye diseases affecting vision, including glaucoma, hereditary optic neuropathies, and ischemic optic neuropathies. Normally, RGCs do not regenerate; thus, RGC loss in these diseases is not reversible. One potential strategy for replenishing lost RGCs in patients is to reprogram stem cells and/or glial cells to functional RGCs. Knowledge about how RGCs are generated during embryonic development will greatly facilitate such efforts. During development, RGCs originate from naïve proliferating retinal progenitor cells (RPCs). Key transcription factors functioning at the different stages of RGC differentiation have been identified, and the mechanisms by which these transcription factors interact with enhancers to regulate target genes and promote RGC formation are being unraveled. These transcription factors likely interact with other factors to carry out their functions, but this is a much understudied area. The current proposal focuses on the factors that interact with Atoh7 to promote RGC formation. Atoh7 is a bHLH proneural transcription factor that is specifically required for RGC genesis. Atoh7 activates downstream genes by binding to E-box sequences in the target gene enhancers. However, multiple proneural bHLH transcription factors are expressed in the developing retina, and they are all capable of binding to similar if not identical E-boxes, yet only Atoh7 is capable of efficiently promoting RGC genesis. Using both ex vivo and in vivo assays, we have now shown that the differences between Atoh7 and other related bHLH transcription factors such as Neurod1 in promoting RGC formation lie within the bHLH domain. We have further narrowed down the responsible differences between Atoh7 and Neurod1 to six amino acid (a.a) residues. The locations of these six a.a. residues suggest that they likely provide interfaces for interaction with additional protein patterners, indicating a likely mechanism for Atoh7 to promote RGC differentiation. Our current proposal aims to identify these interacting proteins and characterize their functions. We will achieve our aims using proximity biotin labeling with our newly generated knock-in Atoh7 allele that expresses a fusion protein of Atoh7 and the biotin ligase BioID2. Our preliminary results demonstrate that this is a very feasible approach. Our specific Aims are: 1) To identify proteins interacting with Atoh7 in the developing retina and to characterize the specificity of the interactions. 2). To investigate the function of Atoh7 interacting proteins in RGC genesis. The proteins we will identify that are associated with Atoh7 will provide new research directions regarding how RGC specific gene regulation is achieved and how the RGC lineage is established. The findings will be significant not only for understanding the fundamental process of retinal cell differentiation but also for guiding efforts to regenerate RGCs to treat related retinal diseases.

NHLBI - National Heart Lung and Blood Institute

Graft versus host disease (GVHD) is the major complication associated with allogeneic hematopoietic stem cell transplantation (HSCT). A critical element of the pathophysiology of GVHD is the failure to reconstitute the regulatory T cell compartment which has been shown to be important for the mitigation of GVHD severity. Re- establishment of an effective regulatory network to counterbalance the pro inflammatory milieu by enhancing regulatory T cell (Treg) survival and suppressive capability therefore remains a major challenge in the field. In preliminary studies, we have demonstrated that the interleukin 27 (IL-27)/IL-27 receptor (IL-27R) signaling pathway plays a critical role in the regulation of CD4+ Treg survival and suppressive capability, and that blockade of IL-27 or the IL-27R results in significantly reduced GVHD lethality, increased CD4+ Treg reconstitution, stabilization of Foxp3 expression, and an increase in CD4+ Treg mitochondrial fitness. In addition, our studies have uncovered a previously unappreciated role for the lysosomal glycoprotein, gamma interferon lysosomal thiol reductase (GILT), by revealing that the regulation of IL-27/IL-27R signaling in CD4+ Tregs is mediated by downstream expression of this glycoprotein. Based on these studies, the overall goal of this proposal is to delineate mechanistic pathways by which absence of IL-27R signaling in CD4+ Tregs promotes their survival, enhances their suppressive capability, and alters the alloreactive donor T cell repertoire. Our overall hypothesis is that signaling through the IL-27R regulates CD4+ Treg survival and that blockade of this pathway augments Treg reconstitution and enhances metabolic fitness. Studies in Specific Aim 1 will delineate mechanistic pathways by which blockade of IL-27R signaling in CD4+ Tregs enhances their ability to prevent GVHD-induced lethality. To address this question, we will employ genetically modified murine models to examine the functional relevance of the mTor and autophagy pathways in mediating the suppressive effects of CD4+ IL-27R/ Tregs as well as determine the effect of IL-27R signaling blockade on mitochondrial metabolism. Experiments in Specific Aim 2 will define the role of GILT in the regulation of CD4+ Treg survival and functional suppressive capability and determine the extent to which absence of GILT phenocopies what is observed with CD4+ IL-27R/ Tregs. We will also delineate the effect of lysosomal expression of GILT on mitochondrial function and oxidative phosphorylation in CD4+ Tregs. Studies in Specific Aim 3 will characterize how absence of IL-27R signaling in CD4+ Tregs alters the alloreactive and regulatory T cell repertoires during GVHD. To address this question, we will employ newly developed bioinformatic pipelines that utilize both single cell paired alpha/beta T cell receptor RNA sequencing and single cell RNA transcriptomics to provide integrated clonal definition and transcriptional profiles for donor T cells residing in GVHD tissue sites. The overall objective of these studies is to develop new insights into the pathophysiology and regulation of GVHD that will foster the development of clinically relevant strategies to mitigate this complication in allogeneic HSCT recipients.

NEI - National Eye Institute

PROJECT SUMMARY Gene therapy for the treatment of autosomal recessive disorders by supplementation with wild-type (WT) copies of the affected gene has been tested in FDA-approved trials. However, strategies for treating autosomal dominant (ad) disorders, which require the removal of a gain-of-function allele through precise genomic repair, have been tested preclinically but have not been evaluated in human subjects. In this proposal, we aim to overcome long standing obstacles to the treatment of RPE65 D477G dominant disorders using autologous induced pluripotent stem cell (iPSC) transplantation. The central hypothesis is that patient-derived iPSC RPE (iRPE) grafts repaired by CRISPR in vitro are a therapeutic option to treat RPE disorders. We will use allele- specific CRISPR-edited RPE65 D477G iRPE to confirm functional repair and differentiation in Aim 1a, and the genomic integrity will be validated via WGS in Aim 1b. The therapeutic potential of iRPE transplantation will be assessed when transplanted into a retinitis pigmentosa preclinical mouse model, Rpe65rd12;Prdcscid. By comparing phenotypes induced by transplantation of repaired iRPE vs. control RPE lines, we will assess whether in vitro CRISPR-repaired iRPE halts disease development in the context of an ad disorder. Our objective is to identify ways to leverage patient stem cells as a tissue source for regenerative medicine. Aim 2 will determine whether patient iRPE repaired in vitro functionally integrate into the retinal circuitry of live mice and rescue vision. Lastly, Aim 3 will determine whether transplanted iRPE is safe and nontumorigenic through long-term analysis.

Avangrid Foundation

Supports STEM education, sustainability, and community development programs in NYSEG, RG&E, and CMP service areas.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary Pseudomonas aeruginosa (Pa) is an opportunistic and increasingly antibiotic resistant Gram-negative bacterium that is one of the major causes of chronic nosocomial infections in the United States. The colonization of Pa within a host is often linked to the bioavailability of nutrients, such as iron, and Pa has multiple iron acquisition pathways that allow it to adapt readily to the variety of environments it may encounter within a human host. Pa responds to these dynamic environments commonly through the use of two-component signal transduction systems (TCSs) that are important mediators of signal transduction and allow pathogens to detect chemical and/or physical changes in the environment in order to control basic cellular processes. Previous studies have identified a biofilm and quorum sensing TCS known as BqsRS (also known as CarRS) that regulates biofilm formation and decay in Pa through the sensing of extracytoplasmic Fe2+ and Ca2+. Among its targets, the BqsRS TCS is known to regulate rhlAB and rhlC, critical genes for rhamnolipid production and biofilm formation that are also known to be connected to iron homeostasis and antibiotic resistance. Moreover, the deletion of either bqsR or bqsS in PAO1 results in a significant increase in biofilm formation but reduced biofilm dispersion, the latter of which is important for downstream infections. These observations highlight the importance of the BqsRS TCS to Pa virulence, but there is a foundational lack of understanding regarding the structure, the selectivity, and the mechanism of this system. The ultimate goal of this proposal is to generate a mechanistic and functional understanding of BqsRS at atomic, molecular, and organismal levels in order to exploit this system as a means of reducing or stemming the virulence of opportunistic pathogens such as Pa. The objectives of this exploratory grant are to determine the structural and molecular characteristics of BqsRS, to define how these properties govern BqsRS metal selectivity and function, and to examine a new role of the BqsRS system in regulating the Feo system in P. aeruginosa. Ultimately, the accomplishment of this exploratory grant will deliver fundamental mechanistic insight into a critical metal-sensing TCS and lay the groundwork for future studies that may be designed to target this system and its homologs for additional bacterial exploits.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY Lung injury can lead to improper repair and regeneration, promoting chronic diseases like emphysema and fibrosis. Following severe injury, basal stem cells migrate into the alveolar niche, displacing local AT2 progenitors and creating a “stem cell collision,” where basal cells outcompete AT2 cells, disrupting normal tissue repair. This impairs the AT2 cells’ ability to restore homeostasis through euplastic regeneration. Our preliminary data suggests that this basal cell invasion generates an injury-induced tissue niche (iTCH) comprised of basal stem cells and Pdgfra+ alveolar fibroblasts (AF1s), which are activated during injury and establish a signaling feedback loop, including Notch and Wnt pathways. In mice, AF1 cells are the primary mesenchymal response to injury, differentiating into AF2 cells. This differentiation is unidirectional, with minimal AF2 proliferation or AF1 reversion. We also found that basal cell invasion is regulated by Trp63 expression and Sox2, which suppress basal cell expansion after injury. Notably, iTCH formation is controlled by Notch signaling in AF1s, not basal stem cells. Loss of Notch signaling in AF1s disrupts iTCH formation and prevents dysplastic repair, a feature observed in human fibrotic diseases, including post-COVID-19 fibrosis. In contrast, chronic diseases such as COPD show altered Wnt signaling. These findings suggest that aberrant signaling in iTCHs could serve as a biomarker for lung diseases. We hypothesize that an emergent niche after acute injury determines whether tissue repair is dysplastic or euplastic by rewiring signaling pathways between lung cell lineages. The study aims to further investigate these pathways to better understand the mechanisms of lung repair.

OD - NIH Office of the Director

Project Summary. We request a BD FACSDiscover S8 Cell Sorter to bring advanced image-based and spectral sorting capabilities to UCLA, enabling high-throughput analysis and isolation of cells based on spatial features, intracellular localization, and cell-cell interactions—capabilities not possible with conventional flow cytometers. Housed in the Broad Stem Cell Research Center and supported by the David Geffen School of Medicine, the instrument will serve NIH-funded investigators across fields including immunology, oncology, developmental biology, and biomedical engineering. The S8’s real- time imaging enables sorting of nanovial compartments based on direct tumor–immune cell contact, spatial RNA localization such as XIST nuclear foci, or the presence of phase-separated RNA droplets in live cells. Its spectral flow cytometry allows flexible, high-parameter panels for identifying rare hematopoietic stem cell subsets, profiling nanoparticle uptake, and assessing complex immune activation signatures without extensive compensation. These features directly support cutting-edge projects such as nanovial-enabled T cell functional screening and sorting based on secreted cytokines, growth or reporter activation. Together, these capabilities will allow researchers to interrogate rare and dynamic cell states with unprecedented precision, advancing efforts to understand and treat cancer, autoimmune diseases, infections, developmental disorders, and enabling next-generation gene and cell therapies.

Best Buy Foundation

Funds teen tech centers and STEM programs preparing youth from underserved communities for tech careers.

NIDCD - National Institute on Deafness and Other Communication Disorders

Human pluripotent stem cells (hPSCs) have been demonstrated to be powerful tools to study human biology and diseases, especially for which human tissue is difficult to access to and biopsy is challenged to obtain. Inner ear is one of organs that is nearly impossible to access without causing damages. Moreover, it is rare to obtain human inner ear biopsy. However, inner ear disorders, including hearing loss and vestibular dysfunction, are one of the most common sensory disorders. Although animal studies have advanced our understanding in hair cells, the underlying cellular processes may differ from those of human. A human cell-based model is therefore needed to progress our understanding of inner ear and the development of therapeutic strategies. Recently, stem cell-derived three-dimensional (3D) inner ear organoids have been reported to mimic certain aspects of inner ear development and disease pathologies in vivo. Despite this potential, there are limitations in the 3D inner ear organoid system to faithfully recapitulate some developmental processes, e.g., morphogen gradients that are critical for proper patterning. Therefore, we first propose to develop an innovative microphysiological system featuring a microfluidic chip that can precisely establish desired morphogen concentration gradients to which large size, 3D organoids are subjected on-chip (Aim 1). We will mediate BMP, WNT, and SHH signaling pathways to model dorso-ventral patterning in otic vesicles as a proof of concept. Results will assist us to understand how to induce the proper dorso-ventral patterning such that a similar strategy can be applied to effectively induce ventralization in the hPSC-based inner ear organoid system. As many inner ear disorders stem from malfunction of or damages in hair cells, we then propose to understand regulatory processes for the hair cell formation with special focus on epigenetic regulatory mechanisms, which is poorly understood, using the hiPSC-derived 3D inner ear organoid system (Aim 2). We propose to generate comprehensive epigenetic and transcriptomic regulatory networks for nature occurring hair cell differentiation and post-damage-induced hair cell regeneration using single cell (sc) muti-‘Omic approaches. Furthermore, we will validate the findings from sc multi-‘Omic approaches by testing the effects of the identified regulatory enhancer regions and genes in hair cell regeneration using CRISPR/dCas9-based assays (Aim 3). This will allow us to mimic epigenetic regulation of gene expression during hair cell formation. This project is not only improving the technology for the organoid system, but also providing the first step towards systematically advancing our knowledge of the role of epigenetics in human hair cell formation and, ultimately, developing therapeutic strategies for damaged hair cells.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY/ABSTRACT Cardiac IKr is a critical repolarizing potassium current shaping the human ventricular action potential. It is conducted by heteromeric assemblies of the human ether-à-go-go-related gene (hERG1) 1a and 1b subunits. These subunits are encoded by alternate transcripts of the hERG/KCNH2 gene and differ only in their amino- terminal regions. hERG1a/1b heteromerization is vital for normal CM function, as the imbalance of subunit expression and/or function results in cellular pro-arrhythmic behaviors. hERG1a/1b assembly is mediated by the co-translational association of the encoding mRNAs in HEK293 cells, cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs), and human myocardium. Evidence suggests that interaction between the nascent proteins is not required for the co-translational complex assembly. This grant's preliminary findings indicate that this complex assembly occurs post-transcriptionally and is promoted by direct interactions between hERG1a and 1b mRNAs governed by their secondary structures. In preliminary studies, RNA binding proteins DDX3X and DDX5 were identified as part of the complex, and purified DDX3X promoted hERG1a/1b mRNAs' association in vitro. In the K99 phase, I will define the mRNA structural features promoting the co-translational association and determine the affinity and energies of the RNA/RNA interaction using in vitro systems, isothermal calorimetry (ITC), mutagenesis, hybrid protein-RNA immunoprecipitation (RIP), and live-cell imaging. I will also determine whether DDX3X and DDX5 affect hERG1a and 1b mRNAs stability, translation, and association in hiPSC-CMs using qPCR, electrophysiology, Western Blot, ribosome profiling, RIP, and single molecule fluorescent in situ hybridization (smFISH). I will use quantitative ITC and in vitro reconstitution approaches to determine the specificity, affinity, and energies of the interaction between purified DDX3X and DDX5 with hERG1a and 1b mRNAs. I will also evaluate if DDX3X and DDX5 promote the association of the mRNAs in in vitro systems. In the R00 phase, I will determine whether the stability, translation, and association of hERG1a and 1b mRNAs are impaired in arrhythmias associated with type 2 long QT syndrome (LQT2). I will use hiPSC-CM disease models to evaluate half-life, translation rate, and association of the mRNAs with qPCR, ribosome profiling, RIP, and smFISH. These experiments will contribute to understanding ion channel biogenesis and elucidate molecular mechanisms underlying LQT2 related arrhythmias. This proposal is designed to fulfill my short-term goals of expanding my skills in cardiovascular research and biophysics and transitioning into the independent phase of my career. This will ultimately allow me to obtain my long-term purpose of linking RNA and ion channel biophysics to translational cardiovascular research.

U.S. National Science Foundation

The Biological Anthropology Program seeks to advance scientific knowledge about the processes that have shaped biological diversity in living and fossil humans and their primate relatives through support of basic research on human and primate evolution, biological variation, and interactions between biology, behavior and culture. The program supports a portfolio of research that demonstrates engagement with biological anthropological and evolutionary theory; includes diverse and interdisciplinary methods in field, laboratory and computational settings; encompasses multiple levels of analysis (e.g., molecular, organismal, population, ecosystem) and time scales from the short-term to evolutionary; and considers the ethical implications and societal impacts of the research. The program also supports a wide range of broader impact activities as part of research grants, including research outcomes with inherent benefit to society, efforts to broaden participation in science, technology, engineering, and mathematics (STEM) training, research and outreach activities and other evidence-based activities developed within the context of the mission, goals and resources of the organizations and people involved. The program contributes to the integration of education and basic research through support of dissertation projects conducted by doctoral students enrolled in U.S. universities. This solicitation specifically addresses the preparation and evaluation of proposals for Doctoral Dissertation Research Improvement Grants (DDRIG). Dissertation research projects in all of the subareas of biological anthropology are eligible for support through these grants. These awards are intended to enhance and improve the conduct of dissertation research by doctoral students who are pursuing research in biological anthropology that enhances basic scientific knowledge.

U.S. National Science Foundation

The Biological Anthropology Program seeks to advance scientific knowledge about the processes that have shaped biological diversity in living and fossil humans and their primate relatives through support of basic research on human and primate evolution, biological variation, and interactions between biology, behavior, and culture. The program supports a portfolio of research that demonstrates engagement with biological anthropological and evolutionary theory; includes diverse and interdisciplinary methods in field, laboratory and computational settings; encompasses multiple levels of analysis (e.g., molecular, organismal, population, ecosystem) and time scales from the short-term to evolutionary; and considers the ethical implications and societal impacts of the research. The program also supports a wide range of broader impact activities as part of research grants, including research outcomes with inherent benefit to society, efforts to broaden participation in science, technology, engineering, and mathematics (STEM) research, training and outreach activities and other evidence-based activities developed within the context of the mission, goals, and resources of the organizations and people involved.

NHLBI - National Heart Lung and Blood Institute

Project Summary Trabecular bone marrow contains two anatomically distinct yet functionally interdependent niches that support hematopoietic stem cells (HSCs): the endosteal niche, which promotes dormancy and self-renewal of long-term HSCs, and the vascular niche, which supports actively cycling short-term HSCs and ongoing hematopoiesis. These compartments coordinate bone remodeling and hematopoiesis, but the mechanisms underlying their integration remain poorly understood due to the anatomical inaccessibility of the bone cavity and the lack of physiologically relevant preclinical models. This proposal aims to develop a biomaterials-integrated bone–marrow microphysiological system (MPS) that recapitulates the structural and functional interdependence of the bone and marrow compartments and enables dynamic analysis of HSC behavior. The platform integrates two advanced biomaterials: demineralized bone paper (DBP), an osteoid-like matrix that supports osteoblast mineralization and osteoclast-mediated remodeling, and an inverted colloidal crystal (ICC) hydrogel scaffold that mimics the sinusoidal architecture of marrow and supports stromal–hematopoietic interactions. The central hypothesis is that integrating these components within a silicon-based perfusion chip will enable high-fidelity modeling of dynamic bone marrow niche processes with precise experimental control and microscopic access. Aim 1 will establish the bone–marrow MPS by seeding BMSCs and osteoblasts into their respective biomaterials, validating niche-specific stromal phenotypes, and recapitulating bone remodeling. CD34⁺ HSCs will then be introduced to assess how integrated versus separated configurations of the bone and marrow compartments differentially regulate HSC behavior. Aim 2 will validate the bone–marrow MPS by recapitulating autologous HSC transplantation scenarios following preconditioning. Donor-matched bone–marrow MPS units will be established, and HSCs derived from a different donor will be introduced with and without fractionated irradiation. By comparing HSC engraftment outcomes, the MPS’s ability to replicate known features of clinical transplantation will be demonstrated. This human-relevant bone–marrow MPS platform will provide new insights into bone–marrow crosstalk, preconditioning regimens, and HSC processes. It offers a scalable, high-resolution system for studying hematopoiesis, transplantation biology, and therapeutic interventions—aligned with NIH priorities in the NOSI: Bold New Bioengineering Research for Heart, Lung, Blood, and Sleep Disorders.

U.S. National Science Foundation

TEMPORARY NOTICE: Program Synopses Changes may occur after the close of the February 1 to March 2, 2009 Window-of-Opportunity.An additional CBET program may be added to the Biomedical Engineering and Engineering Healthcare cluster. This potential program may include topics such as: biosensing, imaging and food processing - - which are all currently handled by existing CBET programs.~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~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 * Advance both engineering and life sciences with biomedical engineering projects that are at the interface of engineering and biomedical sciencesThe BME program supports fundamental, transformative, and discovery research applied to biological systems. The BME projects must * Be fundamental, transformative, and discovery research * Develop novel ideas integrating engineering and life science principles in solving biomedical problems that serve humanity in the long-term * Focus on high impact transforming methods and technologies and 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 Information technology relevant to biotechnology including bioinformatics New novel methods of reducing health care costs through new technologies * Emphasize the advancement of fundamental engineering knowledge, possibly leading to the development of new methods and technologies in the long-term * Emphasize novel application of existing technologies to advance fundamental knowledge of both engineering and life sciences * Highlight multi-disciplinary nature, integrating engineering and the life sciences * Balance theory, mathematical modeling, and experiment * Advance both engineering and life sciences at the discovery-levelThe BME program supports projects in the following BME themes: * Neural engineering (brain science, computational neuroscience, neurotech, cognitive engineering) * Computational modeling, multiscale modeling, biocomplexity * Cardio/pulmonary systems engineering * Gene and drug delivery systems * Cellular and tissue engineering (cellular biomechanics, genetically engineered stem cell differentiation with long-term impact in tissue repair and regenerative medicine) * Biomaterials and biomimeticsBME Program requirement: On the last line of the project summary page, the PI must write the BME theme(s) that he/she is submitting the proposal for. (Please check the list above to determine the BME theme(s) for your proposal.)Answers to frequently asked questions: * The Biomedical Engineering (BME) program supports fundamental, transformative, and discovery research applied to biological systems. * Integration of engineering expertise with life science principles is an essential requirement for advances in this field. * Projects submitted to the BME Program must advance both engineering and life sciences and be at the interface of engineering and life sciences. * The projects can have diagnosis or treatment-related goals in the long-term. The BME program does not support clinical studies. * The long-term impact of the projects can be related to disease diagnosis and/or treatment, improved health care delivery, or product development.The duration of unsolicited awards is generally one to three years. The typical award size for the program is $100,000 for individual investigators or $200,000 for multiple investigators per year (including indirect cost). Small equipment proposals up to $100,000 will also be considered and may be submitted during the submission windows. Any proposal received outside the announced dates will be returned without review.The duration of CAREER awards is five years. The submission deadline for Engineering CAREER proposals is in July every year. Please see the following URL for more information: http://www.nsf.gov/pubs/2005/nsf05027/nsf05027.jsp Proposals for Conferences, Workshops, and Supplements may be submitted at any time, but must be discussed with the program director before submission.Grants for Rapid Response Research (RAPID) and EArly-concept Grants for Exploratory Research (EAGER) replace the SGER program. Please note that proposals of these types must be discussed with the program director before submission. Further details are available in the PAPPG download, available below. Please refer to the Proposal and Award Policies and Procedures Guide (PAPPG), January 2009, (NSF 09-1) when you prepare your proposal. The PAPPG is available for download at: http://www.nsf.gov/publications/pub_summ.jsp?ods_key=nsf091

NHLBI - National Heart Lung and Blood Institute

Project Summary Tissue engineered vascular conduits (TEVCs) offer high potential for treating cardiovascular diseases, such as single ventricle defects, by repairing damaged tissues and improving circulation. Conduits made of realistic tissue components present as long-lasting solutions capable of adapting with the body and integrating with host cells, thus offering enhanced, physiologically mimicking functionality. Bioprinting is an enabling approach toward generating user-designable tissues, with potential for maximizing accommodation for patient- specific needs. However, current bioprinting techniques are restricted in the types of materials that can be used as bioinks, typically relying on artificial materials/modifiers in bioink solutions or extremely high concentrations and acidity to enable printability, which limit biocompatibility and versatility. Many natural, physiological materials remain unprintable, especially with direct inclusion of cells within the bioinks. Moreover, key limitations in existing TEVCs (which are typically not bioprinted) include high incidence of stenosis in patients, thus elevating the risks of utilizing such products as the clinical gold standard. In this proposed study, we will develop highly tunable and customizable TEVCs utilizing a novel bioprinting method capable of directly printing fully physiological materials, including cell-laden tissues. Our method is fast, enabling rapid production of TEVCs with custom features. We will further incorporate universal immunocompatible human induced pluripotent stem cell (iPSC)-derived cells, including endothelial cells, in our bioprinted TEVCs to generate highly biomimicking living vessels with a functional endothelium, which will be conditioned and matured to enhance vessel function prior to implantation experiments. Matured TEVCs will subsequently be implanted in vivo into humanized rats to evaluate performance enhancements. Our study will produce a new generation of TEVCs with significantly enriched functions – custom bioprinted, immunocompatible living vessels for personalized and off-the-shelf capable regenerative therapeutic applications. We aim to develop fundamental advances in tissue engineered vessels for treating single ventricle defects.

U.S. National Science Foundation

The Biotechnology, Biochemical, and Biomass Engineering (BBBE) program deals with fundamental problems involved in the processing and manufacturing of products of economic importance by effectively utilizing renewable resources of biological origin and bioinformatics originating from genomic and proteomic information. The BBBE program emphasizes basic engineering and biological research that advances the fundamental knowledge base that contributes to a better understanding of cellular and biomolecular processes (in vivo, in vitro, and/or ex vivo) and eventually to the development of generic enabling technology and practical application. Quantitative assessments of bioprocesses and their rates at the levels of gene regulation and expression, signal transduction pathways, posttranslational protein processing, enzymes in reaction systems, metabolic pathways, cells and tissues in cultivation, and biological systems including animal, plant, microbial and insect cells, etc. are considered vital to the successful research projects in the BBBE program. Research projects supported through the BBBE program include, but are not limited to: Fermentation technology Enzyme technology Recombinant DNA technology Cell culture technology Ex vivo and therapeutic stem cell culture technology Metabolic engineering Tissue engineering Nanobiotechnology Quantitative systems biotechnologyThe duration of unsolicited awards is generally one to three years. The average annual award size for the program is $100,000 for individual investigators and $200,000 for multiple investigators. Any proposal received outside the announced dates will be returned without review.The duration of CAREER awards is five years. The submission deadline for Engineering CAREER proposals is in July every year. Please see the following URL for more information: http://www.nsf.gov/pubs/2008/nsf08051/nsf08051.jsp.Proposals for Conferences, Workshops, and Supplements may be submitted at any time, but must be discussed with the program director before submission. Grants for Rapid Response Research (RAPID) and EArly-concept Grants for Exploratory Research (EAGER) replace the SGER program. Please note that proposals of these types must be discussed with the program director before submission. Further details are available in the PAPPG download, available below. Please refer to the Proposal and Award Policies and Procedures Guide (PAPPG), January 2009, (NSF 09-1) when you prepare your proposal.

NEI - National Eye Institute

The human nervous system is complex, comprising thousands of functionally distinct neuronal subtypes, each defined by unique gene expression profiles. The timing of cell cycle exit and terminal differentiation plays a critical role in determining neuronal fate. Existing chemical-based birth dating strategies are limited by cytotoxicity, the need for tissue fixation, and incompatibility with transcriptomic profiling. Conversely, single-cell transcriptomic approaches can infer developmental trajectories but do not directly link birth timing to maturation and terminal fate. To address this gap, we propose to develop Birth Labeled sequencing (BLab-seq), a novel transgene-based strategy that integrates non-toxic, fluorescent birth dating with single-cell RNA- sequencing to directly link neuronal birth timing and fate specification in human organoids. Unlike traditional cell lineage reporters, BLab-seq will offer a temporally precise, nontoxic, and multiomics-compatible strategy for studying neurogenesis across all cell types in human organoids—capabilities not currently available with existing tools. To validate BLab-seq and generate new mechanistic insights, we will test BLab-seq using human retinal organoids. Human vision is dependent on the retina, a multilayered neural tissue composed of a diverse array of neuronal classes and subtypes that detect, process, and relay light information. Despite significant progress, critical conceptual gaps in our understanding of human retinal development remain. While studies in model organisms have shown that the seven retinal cell classes are born in broad, temporally ordered windows, these developmental timelines have not been established in humans. Furthermore, the birth timing of the ~130 retinal cell subtypes has not been characterized in any species, and the roles of extrinsic signaling in subtype specification remain largely unknown. Human stem cell-derived retinal organoids offer an experimentally tractable model that recapitulates the developmental timing and cellular diversity of the human retina. Our preliminary studies demonstrate that birth dating in organoids is a valuable strategy to understand developmental mechanisms. Moreover, our findings suggest that retinoic acid and thyroid hormone signaling regulate the developmental timing of photoreceptors and possibly other retinal cell types. The second main goal of this study is to use BLab-seq to determine the birth timing of retinal cell classes and subtypes and to assess how extrinsic signaling influences these processes in human organoids (Aim 2). This aim will validate BLab-seq as a birth dating method, determine the birth order of human retinal cell classes and subtypes, and describe how signaling influences retinal cell birth timing.

Black Girls CODE

Funds STEM education programs for young women of color in underserved communities.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

PROJECT SUMMARY High-dose ionizing radiation (IR), whether from radiotherapy, environmental exposure, or space travel, causes profound and lasting skeletal damage by disrupting bone remodeling through DNA damage, oxidative stress, and vascular compromise, leading to accelerated bone loss, delayed healing, increased fracture risk, and osteoradionecrosis. IR also alters the bone marrow microenvironment, severely impairing bone marrow-derived mesenchymal stem cells (BMSCs), key drivers of bone regeneration, by reducing their proliferation, inducing senescence, and shifting their differentiation from osteogenesis to adipogenesis. Current clinical treatments provide only temporary relief and do not address the underlying cellular damage. Therefore, it is essential to develop strategies that protect BMSCs from IR-induced injury and restore their osteogenic potential to preserve bone architecture and support long-term bone regeneration in IR-related skeletal injuries. Nanomedicine offers transformative opportunities to address IR-induced bone damage by enabling targeted delivery of therapeutic agents at nanoscale. To this end, our laboratory has developed an innovative class of bone-derived nanoparticles (BPs) synthesized from decellularized bone matrix. These BPs offer several advantages, including nanoscale size for efficient cellular uptake, excellent biocompatibility, and a natural bone composition that supports bone regeneration. Our preliminary studies demonstrated that BPs alone can partially mitigate IR-induced cellular damage in BMSCs by restoring critical pathways such as cell cycle progression, DNA repair, and RNA processing. While BPs improved BMSC survival and function following IR exposure, they did not fully restore osteogenic differentiation. To enhance their therapeutic potential, we developed a second- generation system by encapsulating recombinant human Bone Morphogenetic Protein 2 (rhBMP2) within the BPs (termed rhBMP2/BPs). Using tunable crosslinking, we achieved sustained and controlled release of bioactive rhBMP2, creating a platform that significantly enhances osteogenesis in IR-damaged BMSCs by combining the protective properties of bone-derived matrix with osteoinductive effects of rhBMP2. We hypothesize that rhBMP2/BPs will function as a dual-action nanotherapeutic targeting the bone marrow niche to (1) mitigate IR-induced cellular damage by delivering bone-derived matrix proteins that restore key regenerative pathways such as proliferation, DNA repair, and cell cycle progression, and (2) promote sustained osteogenesis through controlled intracellular release of rhBMP2. This prolonged bioactivity is expected to enhance bone structure, restore mechanical strength, and support long-term regeneration. The ultimate goal is to develop and validate rhBMP2/BPs as a bone marrow-targeted therapy that restores BMSC function and promotes effective repair and regeneration of irradiated segmental bone defects, supported by mechanistic in vitro analyses and therapeutic evaluation in clinically relevant animal models. This dual-action approach highlights the translational potential of rhBMP2/BPs for treating IR-related skeletal complications.

NIDCR - National Institute of Dental and Craniofacial Research

Project Summary/ Abstract The goal of the BRE-SPAD initiative at Meharry Medical College is to implement innovative training and funding programs to enhance research capacity and expand Meharry’s national presence in biomedical research. We hypothesize that a comprehensive support program, comprising advanced professional development and grant training, increased technical support, and targeted pilot funding and research incentives, will significantly boost student training, research productivity and overall success at Meharry. To address this hypothesis, we have established three specific aims. Aim 1 will provide advanced professional development and research training to break down psychological barriers, increase confidence and competence in extramural pursuits, improving funding success at all levels. Aim 2 will increase technical support, and protected time and incentives for research activities. Aim 3 will provide dedicated seed funding for research projects, prioritizing projects with high translational potential and those stemming from cross-disciplinary collaborations, supported by grant review committees to guide improvement. Accomplishing these aims will enhance Meharry’s competitiveness in the biomedical research enterprise, fostering a sustainable environment conducive to the development and advancement of faculty and trainee research careers in biomedical science.

U.S. National Science Foundation

Build and Broaden (B2) supports fundamental research and research capacity across disciplines at minority-serving institutions (MSIs) and encourages research collaborations with scholars at MSIs. Growing the science, technology, engineering and mathematics (STEM) workforce is a national priority. National forecasts of the impending shortage of workers with science and engineering skills and essential research workers underscore a need to expand opportunities to participate in STEM research (President's Council of Advisors on Science and Technology, 2012). MSIs make considerable contributions to educating and training science leaders for U.S. economic growth and competitiveness. Yet NSF has received comparatively few grant submissions from, or involving, scholars at MSIs. Targeted outreach activities reveal that MSIs have varying degrees of familiarity with funding opportunities within NSF and particularly within the Social, Behavioral and Economic (SBE) Sciences Directorate. As a result, NSF is limited in its ability to support research and training opportunities in the SBE sciences at these institutions. With its emphasis on broadening participation , Build and Broaden is designed to address this problem. SBE offers Build and Broaden in order to increase proposal submissions, advance research collaborations and networks involving MSI scholars, and support research activities in the SBE sciences at MSIs. Proposals that outline research projects in the SBE sciences that increase students' pursuit of graduate training, enhance PI productivity build research capacity, or cultivate partnerships are especially encouraged to apply. Proposals are invited from single principal investigators based at MSIs and from multiple co-investigators from groups of MSIs. Principal investigators who are not affiliated with MSIs may submit proposals, but must collaborate with PIs, co-PIs, or senior personnel from MSIs and describe how their project will foster research partnerships or capacity-building with at least one MSI as a primary goal of the proposed work. Proposals may address any scientific and cross-disciplinary areas supported by SBE. These areas include anthropology, archaeology, cognitive neuroscience, decision science, ecological research, economics, geography, linguistics, law and science, organizational behavior, political science, public policy, security and preparedness, psychology, and sociology. To find research areas supported by SBE please visit the SBE programs page or visit the NSF funding and awards page.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY The current proposal is based upon our surprising finding that c-Kit is expressed in the kidney collecting duct. c-Kit regulates the proliferation and differentiation of stem cells; however, its role in in fully differentiated epithelial cells, such as in the collecting duct, remains elusive. Thus, this proposal aims to uncover the role of c- Kit receptor signaling in the modulation of kidney collecting duct function. The collecting duct is made up of principal cells (PC), which reabsorb water and salt, and intercalated cells (IC), which secrete protons. The collecting duct epithelial composition is altered in response to biochemical signals, thus affecting whole-body water, electrolyte and acid-base balance. For example, lithium treatment promotes PC differentiation into IC. Fewer PC prevents water reabsorption and leads to the development of nephrogenic diabetes insipidus (NDI), which can lead to severe dehydration and death. However, the precise mechanism by which epithelial cell fate is determined in the adult kidney collecting duct is not well understood. To address this question, I intend to utilize c-Kit “Sash” mice carrying the Wsh/Wsh mutation in a transcriptional element upstream of the KIT gene. This mutation results in reduced c-Kit expression in specific tissues and cells. I demonstrated for the first time that "Sash" mice have significantly reduced c-Kit expression in the collecting duct. I found that male “Sash” mice had an abnormally low urine pH, which could be explained by the fact that these mice have more acid-secreting IC and fewer water-absorbing PC in their collecting ducts. These findings led me to hypothesize that c-Kit receptor signaling in IC is required to maintain the normal cellular composition of the collecting duct, thus allowing the kidney to maintain proper extracellular volume, electrolyte, and acid-base homeostasis. In the current proposal I will determine: a) which isoforms of c-Kit and its ligand are expressed in the collecting duct; b) whether loss of c-Kit in the collecting duct affects renal function, and makes mice more susceptible to NDI, thus, mimicking disease states in the kidney; and c) the gene and protein networks associated with c-Kit receptor signaling in the kidney collecting duct under baseline and lithium-challenged conditions. Since c-Kit receptor activity is required for critical cellular processes including hematopoiesis and mast cell function, universal inhibition of c-Kit is not ideal therapeutically. This makes identifying subpopulations of receptors/ligands that are expressed in specific cell types or tissues critical to developing targeted therapeutics. Furthermore, my work will offer new directions for future studies on c-Kit regulation at the basic cell biological level, as well as providing a novel molecular basis for long-term drug discovery efforts to modulate c-Kit activity in the kidney, and other organs, to attenuate pathological processes caused by c-Kit receptor dysfunction.

California Department of Education

STEM education initiative grants for CA to expand science, technology, engineering, and mathematics programs in K-12 and postsecondary institutions.

Canadian Space Agency

CSA provides grants for space science research, satellite technology development, and STEM education related to space exploration.