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Consolidated Edison Foundation

Supports clean energy education, STEM programs, and environmental sustainability in the greater New York City area.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT___________________________________________________________ Neurodevelopmental disorders (NDDs) like autism, intellectual disability, and ADHD are a global health concern. Progress in understanding the causes of NDDs has been slow and treatment options for core symptoms are limited, partially because these brain disorders currently do not have well-defined biological signatures of pathology that can be utilized in experimental neuroscience paradigms or targeted for intervention. There has been considerable recent progress in identifying statistically significant, high-confidence NDD genetic risk variants, including the heterozygous loss of the 16p11.2 chromosomal region (16pdel). Emerging evidence suggests that 16pdel impacts key prenatal neurodevelopmental processes, though the exact disease mechanisms remain elusive. Patients exhibit neuroanatomical features that could potentially be linked to dysregulated response to signal transduction pathway stimulation. Here, we will investigate how 16pdel fetal brain cells respond to key developmental signaling pathway stimulations at the molecular and cellular levels to identify potential dynamic context-dependent disease mechanisms. To address this question, we will leverage a novel in vitro human stem cell-based platform we developed called the "cell village," which enables large-scale, high-throughput analysis of molecular and cellular responses to cell-extrinsic stimuli across diverse neurotypical control and 16pdel patient donor cell lines. This approach minimizes technical variation and allows for systematic exploration of genetic and cellular variability in a controlled uniform environment. By integrating multi-omic datasets, our study aims to uncover the mechanistic links between gene expression, cellular phenotypes, and pathway activation in 16pdel brain cells in a dish. The proposal is structured around three specific aims: First, we will define the nature and dynamics of signaling dysfunction in 16pdels as hypersensitive, hyperresponsive, and/or hyperactivated in response to stimulation. Second, we will decipher the epigenetic mechanisms underlying pathway dysregulation by investigating chromatin accessibility, methylation patterns, and 3D genome organization in first-of-their-kind multi-omic villages. This aim seeks to determine if 16pdel cells are epigenetically primed for aberrant response to signaling pathway stimulation. Third, we will determine the cellular consequences of dysregulated signaling in 16pdels with a particular focus on neurogenesis and morphogenesis mechanisms. By elucidating the molecular mechanisms driving signal transduction pathway dysregulation in 16pdel fetal brain cells, as well as the impact on cellular functions critical for proper neurodevelopment, this research could illuminate the fundamental neurobiology of a high-confidence genetic risk factor associated with complex NDDs and nominate future targets for intervention, thus improving outcomes for patients and their families.

NCATS - National Center for Advancing Translational Sciences

Project Summary INTS12 is a chromatin interacting subunit of the mammalian Integrator complex that binds to accessible chromatin and controls various aspects of transcription such as elongation and termination. INTS12 interacts with negative elongation factors as well as RNA Polymerase II and regulates its pausing and release into productive elongation. Studies on INTS12 biology in various mammalian systems such as hematopoietic tissues is lacking despite ample evidence of its presence and likely contributions to hematopoietic development and disease. For instance, INTS12 is highly expressed in early stage erythroid progenitor cells during ex vivo erythroid differentiation of human CD34+ hematopoietic stem cells, and it is significantly reduced in the rare hemolytic anemia Congenital Dyserythropoietic Anemia Type IV (CDA IV; CDAN4), which affects young children and renders them transfusion dependent. This proposal will address our core hypothesis that INTS12 function is important for transcription regulation during normal human red cell development and reduced INTS12 levels in CDA IV red cells contributes to ineffective erythropoiesis due to disrupted RNA Polymerase II elongation control. To achieve this, a newly established erythroid progenitor cell line called BEL-A that can be expanded indefinitely, and differentiated to mature erythroid cells will be used. Aim1 will focus on INTS12 chromatin binding in normal wild type (WT) and CDA IV mutant BEL-A cells, and this will be correlated with existing unpublished chromatin accessibility and transcription factor binding data from erythroid stage-matched WT and CDA IV BEL-A cells. Further, the effect of depleting or overexpressing INTS12 on red cell development in WT and CDA IV will also be characterized. In Aim2, we will explore INTS12 functions in transcription by assessing the impact of INTS12 perturbations such as depletion and overexpression on nascent gene expression and RNA Polymerase II occupancy. These data will be correlated with INTS12 occupancy determined from Aim1, and any alterations in nascent transcription leading to changes in RNA Pol II pausing and elongation due to perturbed INTS12 levels will suggest that INTS12 contributes to altered transcription regulation in CDA IV. Transcription elongation by RNA Polymerase II is highly regulated and involves many transcription co- factors and epigenetic mechanisms, some of which are chemotherapy targets for certain hematological malignancies. Further, INTS12 interacts with chromatin using a conserved PHD domain that is being investigated as a potential chemotherapy target using derivatives of a class of compounds known as Amiodarones. The knowledge harnessed from this proposal will thus enable future investigations into INTS12 and Integrator complex biology in erythropoiesis, as well as translational studies on the potential for INTS12 as a therapeutic target in CDA IV patients.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY Hematopoietic stem cells (HSCs) reside in specialized microenvironments in the bone marrow (BM) that comprise multiple cellular constituents, including nerves, with vital regulatory functions. Our previous studies established that the nociceptive nervous system is an essential BM niche component controlling HSC mobilization from the bone marrow into the peripheral blood. Our new preliminary resutls reveal that aging is associated with a progressive loss of nociceptive innvervation in the bone marrow, and that supplementaiton of nociceptive nerve-derived CGRP attenuates the expansion and BM HSCs in aged mice, restores their engraftment ability, and reverses the myeloid-biased differentiation. Based on these findings, we hypothesize that nociceptive nerve-derived CGRP is a critical rejuvenating signal for aged HSCs, and that targeted chemogenetic activation of BM nociceptive neurons using DREADDs can be harnessed to reverse HSC aging in vivo. In the Specific Aim 1, we will determine whether CGRP administration reverses bona fide aging hallmarks and identify the downstream molecular programs that mediate this rejuvenation. In Specific Aim 2, we will investigate whether local activation of BM nociceptive neurons using DREADDs rejuvaentes old HSC in vivo. Together, these proposed studies will shed light into the critical functions of an under-appreciated component of the HSC niche and uncover novel therapeutic strategies for age-associated hematopoietic diseases.

NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

PROJECT SUMMARY Proper embryonic development requires the precise orchestration of a series of well-conserved developmental steps in both space and time. Defects in the temporal unfolding of these steps can give rise to congenital diseases. Surprisingly, the speed of embryonic development is highly species-specific. For instance, among mammals, the duration of embryogenesis ranges from 15 days in mice to 116 days in elephants. Understanding how these species-specific developmental rates are set could have significant translational potential, including accelerating stem cell differentiation for cell therapies or decelerating cellular processes to combat tumor growth and aging. To precisely measure developmental speed across species, we rely on the segmentation clock, a molecular oscillator whose period tightly correlates with the duration of embryogenesis. We have recapitulated the segmentation clock in vitro using mouse and human pluripotent stem cells, therefore enabling cross-species comparisons. Using this experimental platform, we recently found that a key factor regulating developmental speed is the cytosolic NAD+/NADH ratio. This parameter was elevated in mouse cells (fast-developing) compared to human cells (slow-developing). Moreover, experimentally lowering the NAD+/NADH ratio slowed down the segmentation clock, whereas its increase resulted in acceleration. Here we propose to identify the mechanisms that give rise to differential cytosolic NAD+/NADH ratios between species. Cytosolic redox balance is known to be regulated by NADH shuttling systems that oxidize NADH in the cytosol and transfer the reducing equivalents to the mitochondria. Two primary NADH shuttles exist: the glycerol-3-phosphate (G3P) and the malate-aspartate (MA) shuttle. Preliminary data suggest that the G3P shuttle is more active in mouse embryonic cells than in human cells due to differential expression of shuttle enzymes. We hypothesize that species-specific expression of G3P shuttle components in mouse and human embryonic cells drives differences in G3P shuttle activity, thereby establishing distinct cytosolic NAD+/NADH ratios and contributing to the disparity in developmental speed between these two species. In Aim 1, we will directly test the role of NADH shuttles in establishing species-specific NAD+/NADH ratios by comparing shuttle fluxes between mouse and human embryonic cell types, and by manipulating the expression of shuttle components. In Aim 2, we will investigate the regulatory mechanisms underlying species-specific expression of NADH shuttle components, particularly GPD1L, a key enzyme in the G3P shuttle which is expressed in mouse cells but not human cells. By identifying the cis- and trans-regulatory elements controlling species-specific GPD1L expression, we will begin to uncover the genetic basis for differences in developmental speed between species. Overall, the proposed research will provide critical insights into species-specific developmental timing and enhance the utility of human stem cells for therapeutic applications by devising novel strategies for the acceleration of developmental rate.

NCI - National Cancer Institute

PROJECT SUMMARY In cancer and chronic infection, T cells develop into a dysfunctional state called exhaustion because of persistent antigen stimulation. Exhausted T cells upregulate immune checkpoints, display dysregulated metabolism, and progressively lose effector function and the ability to persist and develop immune memory. T cell exhaustion hinders the clearance of pathogens and malignant cells by the immune system and limits the effectiveness of immunotherapies such as chimeric antigen receptor (CAR) T cell therapy. Therefore, understanding how T cells adapt to chronic antigen receptor signaling is critical for developing more effective immunotherapies. A stem-like CD8 T cell subset has been identified in chronic infections and cancers. Stem-like CD8 T cells mediate long-term immunity by self-renewal and replenishing other CD8 T cell subsets. Stem-like properties in T cells are essential for the efficacy of immunotherapies. We have identified key transcription factors that regulate the differentiation of stem-like CD8 T cells. However, the molecular program underlying the adaptation of stem-like CD8 T cells to chronic antigen receptor signaling is incompletely understood. Our recent findings show that the redox sensing KEAP1-NRF2 pathway is critical for the differentiation of stem-like CD8 T cells and adaptation of CD8 T cells to chronic antigen receptor signaling. In the proposed study, we will determine how the KEAP1-NRF2 pathway regulates the adaptation of CD8 T cells to persistent antigen receptor signaling through preventing TCR hyperactivation and promoting metabolic fitness. Our study will shed important new light on the development of more potent and efficacious immunotherapies for cancers and chronic infections. Furthermore, KEAP1 and NRF2 have been extensively investigated as potential drug targets for chronic diseases. Therefore, our findings hold significant promises for informing interventions that aim at modulating this pathway.

NASA Johnson Space Center

The National Aeronautics and Space Administration (NASA) Headquarters Office of Education, in cooperation with the NASA Johnson Space Center and other NASA Centers, is releasing a Cooperative Agreement Notice (CAN) for NASA Internships. On or about January 16, 2013, this CAN will be available electronically through the NASA Solicitation and Proposal Integrated Review and Evaluation System (NSPIRES) at http://nspires.nasaprs.com/ and then clicking the link through the menu listings "Solicitations" to "Open Solicitations." Institutions eligible to respond to this CAN are limited to higher education institutions, nonprogit organizations, and consortia or groups of organizations and institutions serving higher education students, whose mission includes capturing student interest and/or improving student performance in science, technology, engineering, mathematics (STEM) or related fields. The estimated annual value of the award is $3,000,000 to $10,000,000 per year, for a period of performance not to exceed 5 years. It is anticipated that this award will be an indefinite quantity and cost reimbursement cooperative agreement. The recipient of this single award will support sub-agreements at 10 NASA centers delineated by unique cooperative agreement numbers assigned by the NASA Shared Services Center. All centers will follow the same guidelines. The breakdown by center is necessary to ensure costs are tracked correctly. This will allow each NASA facility to easily transfer funding from any technical or administrative organization for support of NASA Internships. The single entity recipient of this award will be responsible for identifying and submitting costs and drawdowns per each center's cooperative agreement number. Due to the variability of this funding model, the successful proposer must have an accounting system considered adequate for tracking and reporting costs applicable to the agreement from multiple funding sources. (See Table 2, Section II for a list of current NASA intern ship locations.) NASA is looking for a flexible and scalable partner who can be innovative and impactful while delivering, sustainable, demonstrable and measureable results. A Notice of Intent (NOI) is requested to assist NASA in assessing the possible response to this CAN; and to determine the number of subject matter experts required for the Proposal Review Panel. NOIs should be submitted by the proposer to NSPIRES by midnight (11:59 p.m.) Eastern Time, February 13, 2013. Instructions for submitting the NOI and the proposal in NSPIRES are found under Section III of this announcement (Proposal and Submission Information). Interested proposers must register with NSPIRES before it can be accessed for use. In order to avoid any conflict of interest in assigning reviewers to proposals, please include a list of participating/partnering institutions in your NOI. All proposals in response to this CAN must be submitted electronically via the NASA Solicitation and Proposal Integrated Review and Evaluation System (NSPIRES) (http://nspires.nasaprs.com ) or Grants.gov. Electronic proposals must be submitted in their entirety by 11:59:59 PM Eastern Time on the proposal due date of March 13, 2013. Respondents without access to the Web or who experience difficulty using the NSPIRES proposal site (http://nspires.nasaprs.com ) may contact the Help Desk at nspires?help@nasaprs.com or call 202-479-9376. This solicitation leading to the award of a Cooperative Agreement is issued pursuant to title 14 CFR Part 1260 for educational and nonprofit institutions and 14 CFR part 1274 for commercial organizations. Notwithstanding the posting of this opportunity at FedBizOpps.gov, Grants.gov, or at both sites, NASA reserves the right to determine the appropriate award instrument for each proposal selected pursuant to this announcement. The points of contact for technical and programmatic questions regarding this CAN are: Technical Officers: Ms. Carolyn Knowles Office of Education NASA Headquarters 300 E Street, SW Washington, DC 20546 Carolyn.knowles-1@nasa.gov Mr. Robert Musgrove Office of Education Johnson Space Center 2101 NASA Parkway Houston, TX 77058 robert.p.musgrove@nasa.gov NASA Internship Solicitation Support: Tamra Ross NASA Research & Education Support 2345 Crystal Drive - Suite 500 Arlington, VA 22202 tkross@nasaprs.com 202-479-9030, Ext. 213 202-479-0511 (fax) Questions regarding this announcement must be presented in writing to Tamra Ross at tkross@nasaprs.com within 30 calendar days of the release date in order that responses may be obtained and disseminated within 5 business days. Oral questions will not be answered due to the possibility of misunderstanding or misinterpretation. Questions and responses will be posted on the NSPIRES website at http://nspires.nasaprs.com .

NEI - National Eye Institute

Scarring of the stroma, the central layer of the cornea, due to Injury or infection, and severe stromal thinning due to keratoconus, cause corneal blindness worldwide. Cornea transplantation is often the only cure for many of these conditions, but limited supply of donor tissue is a major concern. Cell therapy for the stroma, still under development, primarily uses limbal stem cells from donor corneas. Therefore, there is a critical need for treatment of the stroma that will be independent of donor tissues. To address this need, we recently developed human cornea organoids (HCOs) that mimic the fetal cornea. Generated from induced pluripotent stem cells (iPSC) the HCOs present a breakthrough model system of co-differentiating stromal keratocyte, epithelial and endothelial cells in a more cornea-like 3-dimensional extracellular matrix (ECM). Our single cell RNA sequence (scRNA-seq) study shows that HCOs harbor stromal progenitor and fetal corneal keratocyte-like cells which may have the desired long-lasting functionality in the cornea. In addition, we found that HCOs express ECM genes and produce a stroma rich in collagen type III, fibronectin, and other ECM components known to make up the immature corneal stroma. Additionally, as the TGF-𝛽 network is the master regulator of healthy and fibrotic ECM, this network must be specifically regulated in HCOs to maintain its regenerative ECM quality. Therefore, we hypothesize that the HCO is a novel stromal therapy resource and a corneal surrogate for identifying TGF-𝜷 signals that promote healthy but limit fibrotic ECM production. Our preliminary data shows that a mix of stem, progenitor and differentiating cells can be rapidly extracted from the HCO stroma without further monolayer culturing. Injected into decellularized donor corneas the HCO-stromal cells can integrate in the tissue. Second, the extracted ECM from HCOs promote migration in cell culture and corneal wound healing in the mouse. Importantly, as the HCO expresses all major receptors and transcription factors, it is feasible to investigate the TGF-𝛽 network in this model. Aim 1 will determine if extracted HCO-stromal cells will integrate and function in a decellularized donor cornea. Aim 2 will test whether the HCO-stromal cells or the extracted HCO-ECM promote scarless wound healing in the mouse. Aim 3 will identify specific TGF-𝛽 signals that underpin the immature ECM of HCOs. Our findings will develop the HCO as a promising donor tissue-free source of regenerative biomaterial and cells and identify regenerative TGF-𝛽 signals for future treatments of corneal scarring.

NINDS - National Institute of Neurological Disorders and Stroke

Abstract Epilepsy is a severe neurological disease affecting more than 65 million people worldwide and is characterized by unpredictable abnormal electrical discharges resulting in recurrent seizures. About one third of patients with epilepsy suffer from intractable seizures that do not respond to anti-seizure medications (ASMs). Neurosurgical interventions and neurostimulator devices are useful options for only a fraction of patients with drug-refractory seizures, underscoring the urgent need to develop new therapies. One strategy with considerable promise is to engraft new neurons to provide enhanced GABAergic inhibition in an activity-dependent manner. However, use of fetal neurons for cell therapy is associated with practical and ethical issues. Therefore, to overcome such hurdles, in our previous studies, we pioneered the transplantation of human pluripotent stem cell (hPSC)- derived medial ganglionic eminence (MGE)-type human cortical interneurons (cINs) into epileptic mouse brains and demonstrated their integration into dysfunctional circuitry, accompanied by the suppression of seizures and comorbid behavioral abnormalities. Furthermore, more recently, we have determined the optimal stage of human cIN differentiation to ensure maximal integration into host circuitry as well as safety without risk of tumor formation, and developed a method to efficiently generate these safe and highly migratory populations of synchronized early postmitotic cINs from hPSCs in large quantities, bringing cell therapy for epilepsy one step closer to reality. Furthermore, we have successfully tested the efficacy of human early postmitotic cINs in 2 different models of temporal lobe epilepsy (TLE), observing >80% of seizure reduction. With these strong previous studies, now we are ready to embark clinical translation of this novel and restorative therapy for epilepsy patients with limited options. Thus, in this proposed study, we will scale up production of synchronized early postmitotic cINs that are optimal for grafting under cGMP condition. For added safety, we will utilize well- characterized HLA-edited hypoimmunogenic iPSCs to minimize the need for immunosuppression for off-the- shelf use of human cINs. We will also extensively analyze the produced early postmitotic cINs’ phenotype, efficacy, safety, tumorigenesis and biodistribution to seek IND approval. Once we obtain IND approval, we will do a first-in-human clinical trial of early postmitotic cIN grafting with a primary goal of safety analysis, while also checking efficacy as a secondary measure. This will be done in patients with intractable TLE who are candidates for resection while they undergo intracranial EEG to identify the seizure focus without additional invasive steps. Completion of these studies is pivotal for translating this experimental therapy into a viable therapeutic strategy for intractable epilepsy.

NIBIB - National Institute of Biomedical Imaging and Bioengineering

PROJECT SUMMARY The inability to build physiologically relevant in vitro tissue models greatly limits both research capabilities and regenerative therapies. Hydrogels are frequently used to mimic the extracellular matrix (ECM) which surrounds cells in tissue, and the physical properties of these scaffolds can be tailored to individual cell types. These scaffolds are often made from polymers crosslinked by peptides that are substrates for cell-secreted proteases to enable the encapsulated cells to spread and migrate within the matrices. A challenge for these systems is that each cell type within a tissue can have a unique set of ideal matrix parameters. For instance, most tissues are highly vascularized, but endothelial network formation is optimized within matrices that are very soft, while other physiological processes, such as osteogenic differentiation, are typically optimized within stiffer, more highly crosslinked hydrogel matrices. This highlights the need for making hydrogels with specific niches for each cell type. To address this need, we propose fabricating scaffolds in which cell-specific protease activity creates tailored microenvironments around individual cell types. Each cell type expresses a unique combination of proteases, and we have developed novel methods to identify peptides that are specifically cleaved by individual cell types. We are also able to determine whether these peptides are cleaved near the surface of the cell or by soluble proteases that induce bulk matrix degradation. Using a "split-and-pool" peptide synthesis technique, we can generate more than 300 variants of protease-substrate peptides to tune the degradation rates to desired values. We hypothesize that hydrogels crosslinked with peptides with optimal spatiotemporal degradation kinetics will have increased biological performance over existing crosslinking peptides. We will test this hypothesis in two Aims: In Aim 1, we will use a split-and-pool synthesis technique to identify hydrogel crosslinking peptides whose degradation kinetics are optimized for either osteogenic differentiation of human mesenchymal stem cells (hMSCs) or vasculogenesis of human umbilical vein endothelial cells (hUVECs). We will also make peptides which are conjugated with chemically-labile bonds that will enable quantification of the fraction of crosslinks cleaved during culture, which will couple physiological behavior in gels to dynamic changes in hydrogel structure. In Aim 2, we will develop co-culture hydrogels that contain both hMSCs and hUVECs to identify a single peptide that supports both osteogenesis and vasculogenesis within hydrogels. This will pioneer the use of hydrogel crosslinking peptides to simultaneously promote multiple physiological processes within a single system. The proposed research plan combines biomaterial synthesis, analytical chemistry, and cell culture to develop a versatile platform that can be used across tissue systems to improve our ability to model tissues in vitro and regenerate them in vivo.

NIA - National Institute on Aging

PROJECT SUMMARY Dementia, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD), are major contributors to mortality, morbidity, and worldwide healthcare expenditure. FTD is fatal and incurable and represents 10-20% of all dementia cases. Approximately 9% of all FTD cases are caused by MAPT mutations (FTD-tau). Given that there are no effective treatments for FTD (an Alzheimer’s-related dementia), novel therapeutic strategies are urgently needed. Targeting the MAPT gene itself by CRISPR/Cas9 genome editing may provide a curative intervention. We have established a novel dual sgRNA strategy, which can excise the mutant MAPT allele in patient-derived induced pluripotent stem cells (iPSCs). The excision preserves expression from the non-diseased allele. In Aim 1, we will maximize efficiency of our gRNA strategy by identifying sgRNA pairs that excise the MAPT transcription and translation start sites on the mutant allele with high efficiency and no side effects in patient iPSCs and post- mitotic patient-derived neurons in vitro. We will then deliver our optimized editing reagents to an FTD mouse model (PS19) via AAV PhPeB, which cross the blood brain barrier and achieve brain-wide distribution. In Aim 2 we will optimize AAV dosing and determine whether CRISPR editing can reverse pathologic hallmarks of FTD- tau or only prevent their onset. In Aim 3 we will determine how three genes embedded in MAPT affect normal and pathologic tau expression, potentially providing new therapeutic targets, and in any case a useful context for any therapy that aims to alter tau expression or the MAPT locus. With the successful completion of these studies, we will have optimized a candidate gene editing strategy that targets the MAPT mutation, and reaches the highest therapeutic efficacy in human neurons in vitro. We will also determine the therapeutic window in vivo. Our editing strategy will then be ready to pair with human-specific delivery reagents that we and others are developing as they become available. We will have additionally addressed a number of open questions in the field, including whether editing efficiencies in post-mitotic neurons differ from mitotic cells, how to deliver CRISPR/Cas9 with multiple sgRNAs widely throughout the mouse brain, whether it is possible to reverse or arrest clinical phenotypes in symptomatic mice, and the impact of embedded genes on MAPT physiologic and pathologic function. This work will inform our understanding of normal MAPT function and provide proof-of-concept and IND-enabling studies for a novel MAPT CRISPR therapeutic. Our approach is likely also applicable to sporadic FTD-tau and other tauopathies, including progressive supranuclear palsy (PSP), Alzheimer’s disease (AD) and corticobasal degeneration (CBD). Our overarching goal is to accelerate genome editing for neurodegenerative diseases toward the clinic.

NHGRI - National Human Genome Research Institute

Project Abstract Understanding the evolution of regulatory DNA has been impeded both by the lack of functional genomics data available outside of a select group of organisms, as well as by the barriers to implementing genome engineering in diverse organisms for functional analysis. Given the low conservation of the genomic regulatory landscape, this presents a serious impediment to studying genome evolution and limits the value of a phylogenetic approach to understanding human genomic function. We recently developed the Big-IN genome engineering technology to rewrite large genomic loci in-place through delivery of DNA payloads upwards of 160 kb. Here we propose a new synthetic regulatory genomics approach for characterization of the regulatory function of genomic sequence across a phylogenetic tree. We will analyze the activity of a set of model loci in mouse embryonic stem cells by delivering orthologous sequences from 5 vertebrate species. We will employ two strategies to: (i) deliver larger regions (up to 160 kb) including the full gene replacing full orthologous mouse locus; and (ii) combinatorially assess pairs of shorter (~1 kb) candidate enhancer sequences. These data will open a novel approach to understanding genomic regulatory syntax through phylogenetic analysis, as well as a bridge to direct functional assessment of human disease-relevant loci.

NINDS - National Institute of Neurological Disorders and Stroke

ABSTRACT/Project Summary Molecular Mechanisms of Neuronal Connectivity September 8-11, 2026 The proposed meeting to be held at Cold Spring Harbor Laboratory on “Molecular Mechanisms of Neuronal Connectivity” in September 2026 will assemble leaders in the field, junior faculty, postdoctoral fellows and graduate students to discuss new, cutting-edge developments in the areas defined in the meeting title. This proposal seeks support for the fifteenth of a biennial series of meetings held at Cold Spring Harbor Laboratory that has emerged as the premiere meeting in the world for this field. Topics to be discussed for the 2026 meeting will include: programs of circuit wiring, axon targeting, axon regeneration, synapse assembly, the roles of synapses in neural circuits, and glial control of neuronal circuitry and neuronal repair. The planned sessions and invited session chairs will emphasize new technologies and experimental approaches. Approaches include cell biology, biochemistry, genetics, structural biology, bioinformatics, computational biology and electrophysiology. Importantly, the meeting brings together research from multiple systems, including various vertebrate and invertebrate model organisms and human stem cells for investigating neural connectivity and function. Given the broad approaches currently employed in this field, communication among international researchers is essential to advance research and understanding of fundamental mechanisms that regulate wiring of the nervous system and how these mechanisms may relate to the causes and potential cures for neurological disease. Oral presentations will be selected by the session chairs in consultation with the organizers. Each session will be chaired by two leading scientists in the field and the session chairs will give presentations on their cutting-edge research. Selected speakers primarily include graduate students, postdoctoral fellows and junior faculty. Two special lectures will be presented to provide essential background critical to stimulating discussion between scientists working on related but distinct areas. There will also be two poster sessions where the majority of participants can present their work. The meeting will be of moderate size, and we expect 250-350 neuroscientists in attendance.

NCATS - National Center for Advancing Translational Sciences

Abstract The UNC Readiness And Preparation for Informatics and Data Science Careers, or RAPID program, is a 15- week program designed to inspire undergraduates to integrate data science tools into translational science that is rigorous and promotes health outcome optimization across populations. The program components include: 1) didactic training in data science and differential health outcomes in populations 2) mentorship to complete a research practicum, 3) interactions with established investigators who are applying data science tools across the spectrum of translational science and 4) development of a mentoring network comprised of peers, near-peers, staff and faculty. The program is delivered in a hybrid fashion with 2 weeks of preparatory work done by the participant before they arrive at UNC, followed by a 10-week residential summer intensive program. During the 10 weeks, participants are guided through each phase of a data science project from idea formulation to dissemination and are taught choices they can make to incorporate principles of population conscious analysis and rigor into each phase. Participants have the option of 3-weeks of support after they leave UNC to complete and present the research project. Eligible participants are rising sophomore and junior STEM majors. Innovative aspects of the program include use of a conceptual model that gives participants agency to choose their research topic, the application of data science skills in project-based learning, and interactions with community advisory boards to further reinforce communication skills and health outcome optimization across populations.

U.S. National Science Foundation

Cultivating Cultures for Ethical STEM (CCE STEM)funds research projects that identify (1) factors that are effective in the formation of ethical STEM researchers and (2) approaches to developing those factors in all the fields of science and engineering that NSF supports. CCE STEM solicits proposals for research that explores the following: What constitutesresponsible conduct for research (RCR), and which cultural and institutional contexts promote ethical STEM research and practice and why?' Factors one might consider include: honor codes, professional ethics codes and licensing requirements, an ethic of service and/or service learning, life-long learning requirements, curriculaor memberships in organizations (e.g.Engineers without Borders)that stress responsible conduct for research, institutions that serve under-represented groups, institutions where academic and research integrity are cultivated at multiple levels, institutions thatcultivate ethics across the curriculum, or programs that promote group work, or do not grade. Do certain labs have a culture of academic integrity'? What practices contribute to the establishment and maintenance of ethical cultures and how can these practices be transferred, extended to, and integrated into other research and learning settings? Successful proposalstypicallyhavea comparative dimension, either between or within institutional settings that differ along these or among other factors, and they specify plans for developing interventions that promote the effectiveness of identified factors. CCE STEM research projects will use basic research to produce knowledge about what constitutes or promotes responsible or irresponsible conduct of research, and how to best instill studentswith this knowledge. In some cases, projects will include the development of interventions to ensure responsible research conduct. Proposals for awards from minority-serving institutions (e.g. Tribal Colleges and Universities, Historically Black Colleges and Universities, Hispanic-Serving Institutions, Alaska Native or Native Hawaiian Serving Institutions), women's colleges, and institutions primarily serving persons with disabilities are strongly encouraged. Proposals including international collaborations are encouraged when those efforts enhance the merit of the proposed work by incorporating unique resources, expertise, facilities or sites of international partners. The U.S. team's international counterparts generally should have support or obtain funding through other sources.

U.S. Mission to Zimbabwe

Culture of Research and University Exchanges Prep program (CRUX) in One Health and Agricultural STEM

U.S. National Science Foundation

Cyber-Enabled Discovery and Innovation (CDI) is NSF s bold five-year initiative to create revolutionary science and engineering research outcomes made possible by innovations and advances in computational thinking. Computational thinking is defined comprehensively to encompass computational concepts, methods, models, algorithms, and tools. Applied in challenging science and engineering research and education contexts, computational thinking promises a profound impact on the Nation s ability to generate and apply new knowledge. Collectively, CDI research outcomes are expected to produce paradigm shifts in our understanding of a wide range of science and engineering phenomena and socio-technical innovations that create new wealth and enhance the national quality of life. CDI seeks ambitious, transformative, multidisciplinary research proposals within or across the following three thematic areas: From Data to Knowledge: enhancing human cognition and generating new knowledge from a wealth of heterogeneous digital data;Understanding Complexity in Natural, Built, and Social Systems: deriving fundamental insights on systems comprising multiple interacting elements; andVirtual Organizations: enhancing discovery and innovation by bringing people and resources together across institutional, geographical and cultural boundaries. With an emphasis on bold multidisciplinary activities that, through computational thinking, promise radical, paradigm-changing research findings, CDI promotes transformative research within NSF. Accordingly, investigators are encouraged to come together in the development of far-reaching, high-risk science and engineering research and education agendas that capitalize on innovations in, and/or innovative use of, computational thinking. Research and education efforts around the world are beginning to address various aspects of the CDI themes, and CDI projects are expected to build upon productive intellectual partnerships involving investigators from academe, industry and/or other types of organizations, including international entities, that advance CDI objectives within the rapidly evolving global context. Congruent with the three thematic areas, CDI projects will enable transformative discovery to identify patterns and structures in massive datasets; exploit computation as a means of achieving deeper understanding in the natural and social sciences and engineering; abstract, model, simulate and predict complex stochastic or chaotic systems; explore and model nature s interactions, connections, complex relations, and interdependencies, scaling from sub-particles to galactic, from subcellular to biosphere, and from the individual to the societal; train future generations of scientists and engineers to enhance and use cyber resources; and facilitate creative, cyber-enabled boundary-crossing collaborations, including those with industrial and international dimensions, to advance the frontiers of science and engineering and broaden participation in STEM fields. Two types of CDI awards will be supported as a result of the FY 2010 CDI competition:Type I awards will require efforts up to a level roughly comparable to: summer support for two investigators with complementary expertise; two graduate students; and their collective research needs (e.g. materials, supplies, travel) for three years.Type II awards will require larger (than Type I) efforts up to a level roughly comparable to: summer support for three investigators with complementary expertise; three graduate students; one or two senior personnel (including post-doctoral researchers and staff); and their collective research needs (e.g. materials, supplies, travel) for four years. The integrative contributions of the Type II team should clearly be greater than the sum of the contributions of each individual member of the team.In subsequent years, subject to availability of funds, funding opportunities will be provided for three classes of awards, Types I and II as defined above, and Type III as defined below:Type III awards will require the engagement of larger (than Type II) multidisciplinary teams, roughly comparable to multiple senior investigators with complementary expertise, multiple graduate students, several senior personnel, and their collective research needs (e.g. materials, supplies, travel) for up to five years. As for Type II awards, the integrative contributions of the Type III team should be clearly greater than the sum of the contributions of each individual member of the team.

Danaher Foundation

Funds STEM education, health, and community development through targeted philanthropy.

U.S. National Science Foundation

The goal of this activity is to foster novel, transformative, multidisciplinary approaches that address the use of large data sets to create actionable knowledge for improving STEM teaching and learning environments (formal and informal) in the medium term, and to revolutionize learning in the longer term. These approaches will involve the work of learning scientists, STEM disciplinary experts, computer scientists, statisticians, database experts and educational researchers who design and study learning environments. Among the potential benefits of integrating approaches from these disciplines are improving student learning and engagement, optimizing personalized instruction, and supporting rapid decision making to help educators respond more effectively to the learning needs of individuals and groups of learners in multiple settings. These approaches may be risky but should have the potential to rapidly advance the field. The scope of this activity does not include infrastructure development focused on data base design and development for education domains. The new approaches envisioned in this solicitation will require the generation and use of data that range from micro-level data on individual learners, to data from online learning sources (such as massively open online courses), to meso-level data from the classroom that provide information to students and teachers about how learning is progressing, to macro-level data such as school, district, state, and national data, including data from federal science and policy agencies. Participants in the Ideas Lab, selected through an open application process, will engage in an intensive five-day residential workshop, the development of multidisciplinary collaborative proposals through a real-time and iterative review process, and, for the participant teams invited to submit full proposals, the subsequent submission of full proposals.

Datadog Foundation

Funds STEM education and tech career pathways for youth in underserved communities.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

PROJECT SUMMARY Wound healing is a critical physiological process essential for restoring tissue homeostasis from damage and infections. However, many aged people or individuals with chronic conditions often experience delayed or defective wound repair. In the United States alone, these nonhealing wounds cause significant economic burdens, incurring more than $25 billion annually in healthcare costs. A major gap contributing to this issue is the incomplete understanding of complex cellular interactions during wound healing. Cutaneous wound repair is primarily mediated by the epithelial stem cells within the epidermis and hair follicles, whose regeneration and differentiation capacity are supported by diverse cell types forming their niche. While immune cells play pivotal roles in infection control and debris removal, the inflammatory conditions can impair stem cell function. Thus, how epithelial stem cells achieve self-renewal and differentiation within a highly inflammatory environment in injured tissues remains unclear. Addressing this gap is pivotal for advancing our knowledge of immune tolerance, barrier integrity, and wound repair biology. This proposal aims to elucidate how epithelial stem cells modulate their immunological niche to adapt to inflammatory environments and drive wound repair. Our preliminary data indicate that upon injury, the epithelial stem cells residing in the hair follicles activate robust immune-modulatory capabilities, such as upregulating CD80 expression. Importantly, these cells employ this capacity to establish close interactions with regulatory T (Treg) cells, forming a protective niche in the wound site that shields hair follicle stem cells from inflammatory damage. Moreover, we discovered an unconventional mechanism that can directly induce and maintain Foxp3 expression in wound-infiltrating effector T cells. Based on these preliminary findings, we hypothesize that: hair follicle stem cells induce effector T cells within wounds to directly differentiate into Treg cells, which build a protective niche and regulate inflammatory responses crucial for epithelial stem cell function during wound repair. Built on this hypothesis, our first objective is to identify the precursors of Treg cells induced during wound healing. Next, we will delineate the receptors on T cells that respond to CD80 signals from epithelial stem cells to drive Treg induction. Last, we will elucidate the molecular mechanisms by which CD80 stabilizes Foxp3 expression in effector T cells. Together, these studies will unveil a non-canonical mechanism of Treg induction and shed light on the remarkable immune modulatory activity of epithelial stem cells during wound repair. Ultimately, this work may uncover new strategies for improving non-healing wounds.

NCI - National Cancer Institute

SUMMARY Epigenetic complexes are composed of catalytic core enzymes and accessory proteins that work together to regulate gene expression and contribute to cancer development. Most existing therapies target the catalytic cores, often leading to widespread chromatin disruption and unwanted toxicity. In contrast, selectively modulating accessory proteins that fine-tune complex activity and chromatin targeting may provide a more precise and safer therapeutic strategy, yet their functions and potential as drug targets remain largely unexplored. This project focuses on acute myeloid leukemia (AML), a highly aggressive cancer characterized by the uncontrolled proliferation of immature myeloid cells. With over 20,000 new cases each year in the U.S. and a low survival rate of about 30%, there is an urgent need for more effective targeted therapies. Menin inhibitors, which block the Menin-KMT2A interaction, have shown promise in KMT2A-rearranged (KMT2A-r) and NPM1-mutant AML, but emerging resistance highlights the need for deeper insight into Menin-mediated gene regulation. Through an unbiased, reporter-based CRISPR screen, we identified JADE2, an epigenetic accessory component of the KAT7 histone acetyltransferase complex, as a novel regulator of KMT2A-Menin target genes. Our extensive preliminary data demonstrate that JADE2 is a unique component of the KAT7 complex that is selectively required for KMT2A-r AML and modulates the response to Menin inhibition. Importantly, unlike the enzymatic core KAT7, JADE2 depletion does not affect global histone acetylation or normal hematopoietic stem and progenitor cells, highlighting its potential as a selective target. Moreover, saturated CRISPR tiling screens and domain truncation analyses have mapped the regions of JADE2 responsible for chromatin targeting and interaction with the Menin-KMT2A complex, revealing potential druggable sites. The goal of this project is to define how JADE2 regulates leukemia-driving gene programs and therapeutic response in AML, and to characterize its key functional domains that could be leveraged for future drug development. To achieve this, we will first define how JADE2 recognizes and binds chromatin and determine its direct effects on gene regulation using an acute protein degradation system (Aim 1). We will then elucidate how JADE2 interacts with the Menin-KMT2A complex and controls its target genes through integrated biochemical, genetic, and genomic approaches (Aim 2). Finally, we will assess how JADE2 influences the AML response to Menin inhibition and test the therapeutic potential of combined JADE2-Menin targeting in preclinical models (Aim 3). We will use New Approach Methodologies whenever possible, including cell-based, genomic, and biochemical systems. However, these approaches cannot adequately model AML progression and therapeutic response in vivo, necessitating the limited use of animal models in this project. Together, these studies will address critical knowledge gaps and have high impact by uncovering new mechanisms of gene regulation in AML and establishing JADE2 as a promising, druggable target for therapeutic development.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

(PLEASE KEEP IN WORD, DO NOT PDF) Terminal differentiation of erythroid cells occurs in the erythroid-specific niches. The most studied erythroid niche is the erythroblastic island (EBI), which comprises a central macrophage surrounded by developing erythroblasts. While studies over the past decades have identified many genes that are functionally important for EBI, the field faces major caveats. Current knowledge of EBI is predominantly derived from studies of in vitro reconstitution of mixed cell populations that do not recapitulate in vivo niches. In addition, the EBI compositions in human hematopoietic tissues are unknown. In this project, we aim to uncover the anatomy, composition, and functions of EBIs in mice and humans using unbiased approaches through multiple spatial mapping technologies. Through spatial transcriptomic studies, we revealed a higher positive spatial correlation between erythroid cells and C1q+ macrophages than with other macrophages, suggesting that C1q+ macrophages are likely the EBI macrophages in mice. This strong positive correlation between C1q+ macrophages and erythroid cells was also observed in newborn bone marrow and adult spleen under physiologic and stress conditions. We applied the same technologies to human hematopoietic tissues. In contrast to mice, we did not observe a strong positive correlation between erythroid cells and C1q+ or other macrophages in the human hematopoietic tissues. Instead, there is a strong association between erythroid progenitors and maturing erythroid cells. This erythroid self-assembled EBI structure was recapitulated in a human induced pluripotent stem cell (iPSC)-derived bone marrow organoid model. Furthermore, we identified ICAM4 as a critical erythroid surface protein that maintains erythroid-centered EBIs in humans. These preliminary studies uncover unique erythroid niches in mice and humans. Based on this evidence, we hypothesize that mouse and human EBIs have distinct structures and molecular features that help sustain terminal erythropoiesis. In this project, we propose to investigate the composition of macrophage-centered EBIs and the mechanisms of C1q in EBI macrophages in hematopoietic tissues in mice. The same approaches will be used to study ICAM4 and erythroid self-assembled EBIs in humans. Furthermore, EBI responses and their molecular mechanisms under stress and disease conditions in mice and humans will also be investigated. The success of this project will not only advance the understanding of red cell biology but also offer invaluable insights into hematopoiesis as a whole.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

The adrenal cortex is a vital endocrine organ that produces steroid hormones essential for the body's homeostasis. Its organization into three concentric zones enables spatially regulated production of distinct adrenal hormones, a process known as functional zonation. Structural or functional defects in the adult cortex cause primary adrenal insufficiency (PAI), a life-threatening condition affecting millions with no permanent cure, while developmental disruptions in adrenal formation or zonation can lead to congenital adrenal disorders and tumors. In rodents, zonation is established perinatally via centripetal migration and stepwise “transdifferentiation” of subcapsular progenitors within the definitive zone (DZ), regulated by opposing actions of WNT-activating signals from outer capsule (Cap) cells and adrenocorticotropic hormone (ACTH). However, species-specific differences in adrenal organogenesis and steroidogenesis limit the translational value of rodent models for human PAI. To bridge this gap, we developed the first human adrenal organoid model from induced pluripotent stem cells (iPSCs) that recapitulates adrenal development both in vitro and in vivo. This proposal aims to exploit this platform to define and assess the therapeutic relevance of cellular and endocrine/paracrine signaling mechanisms regulating adrenocortical development, with the goal of transforming treatment of life-threatening adrenal diseases. In humans, adrenal cortical zonation begins prenatally, forming three zones: the DZ, the glucocorticoid (cortisol)-producing transitional zone (TZ), and the androgen-producing fetal zone (FZ), which correspond to the functional zones of the adult adrenal cortex. Notably, our organoids can be reliably directed to produce CD10/MME⁺ DZ-like cell (DZLC) progenitors that exhibit striking similarity to in vivo human DZ cells. DZLCs can be further differentiated into TZ-like cells (TZLCs) through combined stimulation with RSPO3 (a Wnt- ligand dependent potentiator of Wnt signaling) and ACTH, and subsequently into FZ-like cells (FZLCs) with ACTH alone. Exogenous RSPO3 is dispensable when DZLCs are co-encapsulated with iPSC-derived RSPO3- secreting Cap-like cells (CapLCs), which mimic the native capsule and enable ACTH-driven transdifferentiation of DZLCs into TZLCs. This contrasts with rodents, where ACTH promotes and WNT suppresses TZ fate. Thus, our in vitro directed transdifferentiation data support the central hypothesis that prenatal human adrenocortical homeostasis is orchestrated by DZ progenitors within a capsular niche that, through self-renewal and transdifferentiation, give rise to both TZ and FZ under coordinated control of WNT and ACTH signaling. Supporting this, our preliminary data show that encapsulation of DZLCs with CapLCs restores functional zonation after transplantation into a hemi-adrenalectomized immunodeficient mouse model, resulting in a long-lived adrenal cortex producing both cortisol and androgens in an ACTH responsive manner. Leveraging our adrenal organoid platform, we will determine whether these progenitor-derived populations can integrate into the host endocrine axis to fully restore adrenal function in vivo.