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MBD4 Driven AR Reprogramming and Luminal Lineage Specification in Prostate Cancer

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NCI - National Cancer Institute

Project Summary/Abstract CANDIDATE: I am a postdoctoral fellow in Dr. Christopher Barbieri’s laboratory at Weill Cornell Medicine, where I investigate the molecular determinants of prostate cancer progression. My PhD training at Tianjin Medical University focused on androgen receptor (AR) signaling and therapy resistance. At Weill Cornell, I have advanced my expertise in high-throughput genomic and epigenomic analyses. My career development plan focuses on acquiring skills in single-cell transcriptomics and epigenomic profiling to prepare for an independent faculty position in translational prostate cancer research. RESEARCH: In the normal prostate, AR signaling maintains luminal identity and drives growth-suppressive programs; however, during tumorigenesis, AR is co- opted into oncogenic programs that drive malignancy. Preliminary data from my genome-wide approach with an unbiased CRISPR-screen have identified MBD4, a methyl-CpG binding protein, as a pivotal regulator of these opposing AR programs. Loss of MBD4 redirects AR activity away from growth suppression toward oncogenic programs by altering FOXA1 binding. In this proposal, I will (Aim 1) define the molecular mechanisms by which MBD4 loss modulates AR function through cell-based assays, organoids, and in vivo models; (Aim 2) elucidate MBD4’s role in maintaining prostate luminal specification using single-cell transcriptomic and functional studies; and (Aim 3) characterize the temporal dynamics of MBD4 downregulation during the transition to prostate cancer through integrated single-cell RNA and targeted methylation profiling. These studies will test whether MBD4 functions as a molecular switch controlling AR’s dual programs and will identify novel therapeutic strategies for precision AR-targeted therapy. ENVIRONMENT: Weill Cornell Medicine is internationally recognized for its excellence in prostate cancer research and provides cutting-edge genomic, epigenomic, and single-cell analysis platforms. Because of the bioinformatics relevance of the project, I have included Dr. Andrea Sboner as a co- mentor; his expertise in computational genomics and multi-omics analysis will be essential for guiding the study’s bioinformatics aspects. My advisory committee also includes Dr. Yu Chen from Memorial Sloan Kettering Cancer Center, whose expertise in prostate cancer organoid modeling and epigenetic regulation provides invaluable insight, and Dr. David Rickman, a leading authority in cellular transitions and lineage plasticity. The combined expertise of my mentors and advisors, along with the state-of-the-art resources at Weill Cornell Medicine, will strongly support my successful transition to an independent research career.

Up to $152K
2028-05-31
health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Measuring Micro and Nanoplastics in Environmental Samples Workshop

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NIEHS - National Institute of Environmental Health Sciences

ABSTRACT The Measuring Micro- and Nanoplastics in Environmental Samples Workshop (“the Workshop”) will be held as part of a Great Lakes Microplastic and Health Symposium (June 17-18, 2026) in Rochester, New York. This Workshop aims to pool existing expertise, establish new collaborations, and prioritize future needs for characterizing micro- and nanoplastics (MNP) in complex environmental matrices relevant to health research in the Great Lakes ecosystem. This Workshop will bring together national experts on MNP analysis with researchers studying the interactions between Great Lakes ecosystems (particularly water and air) and health. The Workshop will be hosted by two multidisciplinary centers that are part of the NIH/NSF Centers for Oceans and Human Health program. The University of Rochester and Rochester Institute of Technology co-host the Lake Ontario MicroPlastics (LOMP) Center, a transdisciplinary hub for research, translation and engagement on how MNPs affect human health and the Great Lakes environment (particularly water and near shore air). The Great Lakes Center for Fresh Water and Human Health is based at the University of Michigan (the Great Lakes Center). Its central goal is to better understand the increasing risks that cyanobacterial harmful algal blooms (cHAB) pose to freshwater ecosystems and human health. One aspect of the Great Lakes Center’s research is to explore the association of aerosolized microplastics and cHABs. Fostering collaboration and scientific exchange between the Great Lakes Center, LOMP, and national experts studying MNPs is one example of how this workshop may have long-term impacts on regional MNP research collaborations that may yield results of global significance. The Workshop has three objectives: 1) Bring together scientists from multiple laboratories and institutions to present new findings, identify methodological challenges, and share analytical approaches to better understand environmental exposures to MNPs and their potential impact on human and environmental health; 2) Develop new collaborations between researchers and trainees across institutions, both regionally and nationally; and 3) Identify priorities and opportunities for analytical advances to support this rapidly growing field. The objectives will be met through a Workshop format with a limited number of participants (30-40) to encourage close interaction. The requested R13 conference funds will be used to pay for expenses for the June 17 Workshop, including travel expenses for trainees, invited experts, and researchers from other institutions. R-13 support will also enable these attendees to participate in the full Great Lakes Microplastic and Health Symposium, to be held on June 18 at the University of Rochester’s Memorial Art Gallery, that will include a larger number of researchers, trainees, and community partners (120-150) on a broad range of topics related to Microplastics and Health with a focus on the Great Lakes region.

Up to $24K
2027-03-31
health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Measuring motivation in people with aphasia: Conceptual foundation and item development

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NIH

Significance to the VA: Veterans experience strokes more frequently than non-Veterans. One of the most debilitating consequences of a stroke is aphasia, a chronic language disorder that affects one third of stroke survivors. While individuals experience a degree of spontaneous recovery within the first 6-12 months post- stroke, most individuals do not fully recover. Continued neuroplastic change to the language system is conferred via long-term behavioral speech-language treatment which is most effective at high doses. Unfortunately, Veterans receive considerably less treatment than best-practice guidelines. Motivation is likely a major contributor to this gap in clinical care. In fact, the VA Clinical Practice Guidelines for Management of Stroke Rehabilitation cite motivation as a barrier to post-stroke rehabilitation and recommend that clinicians assess motivation. However, there are no motivation-based measures with validity evidence in the context of aphasia rehabilitation, creating a critical gap in clinicians' ability to assess and ultimately intervene upon motivation to optimize the amount of treatment Veterans with aphasia receive. Innovation and Impact: This proposal aims to address this gap by modifying an existing measurement tool that, with appropriate adaptations, can identify causes of suboptimal motivation in the context of aphasia rehabilitation. The measure is grounded in self-determination theory, a well-studied theory of motivation that finds that optimal motivations (described as “autonomous”) lead to improvements in health behavior and well- being, and bolster cognitive functions associated with aphasia treatment response. Autonomous motivations are driven by contexts that support three basic psychological needs (BPNs). Measures of BPNs can identify underlying causes of suboptimal motivation and guide interventions that improve motivation – a critical variable that can increase the dosage of treatment and enhance cognitive skills key to treatment response. Specific Aims and Methodology: This proposal is guided by state-of-the-art guidelines for measure development. In Aim 1, speech pathologists and researchers (n = 30) will be presented with the unmodified scale via survey and identify irrelevant or missing items. An expert panel will modify or develop items using survey data. In Aim 2, Veterans with aphasia (n = 7-10) will be presented with the scale modified in Aim 1. Via cognitive interviewing, Veterans will identify items they find difficult to understand, irrelevant, or missing. An expert panel will modify or develop items using cognitive interview data. In Aim 3, Veterans with aphasia (n = 25) will complete the modified scale to generate validity evidence that can support its use in future research. Path to Translation/Implementation: This proposal constitutes the initial steps of a productive and programmatic line of research evaluating the effect of BPN-focused motivational interventions on aphasia treatment outcomes in a single-subject investigation (CDA-2) and large-scale efficacy research (MR Award). This work will enable clinicians to assess motivation as advised by VA Clinical Practice Guidelines. Existing frameworks of rehabilitation (e.g., the Rehabilitation Treatment Specification System) can aid researchers in using the scale to identify treatment ingredients that optimize motivation, a variable central to outcomes. Immediate and Long-term Career Goals: The applicant is a speech pathologist and an advanced fellow in geriatrics in the Geriatrics Research, Education, and Clinical Center at VAPHS, with experience in aphasia rehabilitation and research. During the CDA-1, mentorship and structured training in measurement theory, qualitative research, motivational science, and professional development will support the completion of the proposed CDA-1 and the applicant's career goals to become an independent VA clinician-scientist supported by VA Merit Review and NIH/NIDCD award mechanisms. The applicant's long-term research program will (1) identify neurocognitive and psychological mechanisms underlying aphasia recovery and (2) determine how treatment ingredients can be modified to maximize aphasia treatment outcomes at the individual level.

2028-06-30
health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Mechanisms and Predictions of Interindividual Variability in Drug Pharmacokinetics and Adverse Drug Reactions

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NIGMS - National Institute of General Medical Sciences

Predictions of drug disposition and toxicity from preclinical data, estimation of risk of drug-drug interactions and simulation of drug exposures in humans are essential for safe and effective drug development and clinical pharmacology. Despite decades of research, significant gaps still remain in translating preclinical findings to clinical drug development and practice. As a result, about 90% of drug candidates that enter Phase I clinical trials fail during development. In addition, uncertainty regarding the disposition characteristics of approved drugs often remains after drug approval leading to post marketing studies and label revisions. This wastes resources, leads to unnecessary risk to patients and limits access to life saving medications for specific patient populations. My laboratory works to bridge the knowledge gaps in translational science via mechanistic in vitro studies, mass spectrometry based proteomics experiments and state-of-the art in silico modeling. We develop novel proteomics methods to understand formation of drug adducts by small molecule drugs, evaluate how drug-protein and protein-protein interactions within a cell alter drug distribution and the activity of drug metabolizing enzymes, and assess how genetic variability and individual biology such as sex, disease and age alter drug exposures in tissues and in blood. Central questions of my research program include: What mechanisms cause significant under and overpredictions of drug exposures and drug-drug interactions in humans? Which individual factors define interindividual variability in drug-protein adduct formation making certain individuals highly susceptible? What mechanisms lead to changes in drug clearance in specific populations and between individuals? Answering these questions will advance developing individualized therapy and enable connecting observable patient specific factors with decisions of drug dosage adjustments. Our long term goal is to improve the preclinical, translational and computational methodologies used to predict and evaluate drug disposition and adverse drug reactions. Our current studies are focused on 1) development of innovative proteomic methods for discovery, characterization and quantification of protein adducts in simple and complex biological matrices; 2) evaluation of the role of fatty acid binding proteins in modulating tissue drug distribution and drug clearance and 3) developing novel physiologically based pharmacokinetic models to predict drug disposition in specific populations including vulnerable patients. Our studies advance innovative areas such as how intracellular binding proteins influence drug efficacy, and provide unprecedented insight into mechanisms of enzyme inactivation and quantitative relationships between adduct formation and metabolic activity in the liver. Our research will also provide open and accessible cutting-edge tools for high-dimensional proteomics data and novel PBPK models for prediction of drug disposition in specific patient populations. Our work promises to decrease failure rate during drug development and lead to expanded access to approved medications in specific patient groups through improved quantitative systems biology approaches.

Up to $389K
2031-04-30
health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Mechanisms of cryptococcal IRIS

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NIAID - National Institute of Allergy and Infectious Diseases

Project Summary Due to the progressive depletion of CD4+ T cells, HIV/AIDS patients are more susceptible to infection of Cryptococcus neoformans, an encapsulated fungus that is listed by WHO as a pathogen of critical priority. An estimated 112,000 people die from C. neoformans infections globally each year. C. neoformans is a leading cause of mortality among HIV/AIDS patients. Antiretroviral therapy (ART) can rapidly restore CD4+ T cells in HIV/AIDS patients, representing a major advance in the treatment of HIV-infections. However, the rapid recovery of CD4+ T cells in HIV/AIDS patients that co-infected with C. neoformans after initiation of ART often causes an exaggerated inflammatory response in the central nervous system (CNS), termed immune reconstitution inflammatory syndrome (IRIS). Cryptococcal IRIS is considered as a life-threating condition, as it can lead to a high mortality rate during ART among HIV/AIDS-associated IRIS patients who have a cryptococcal infection. Clinical studies have shown that cryptococcal IRIS is associated with a substantial CNS recruitment of immune cells and enhanced secretions of inflammatory cytokines. However, the cellular and molecular mechanisms involved in cryptococcal IRIS are poorly understood. In particular, it remains to be determined which leukocyte subset(s) and cytokine(s) mediate the death during cryptococcal IRIS and how CD4+ T cell responses are regulated during cryptococcal IRIS. These questions are hard to be answered without animal studies. Using a novel murine model of C. neoformans infection to closely mimic HIV/AIDS-associated cryptococcal IRIS, we will define the mechanisms of cryptococcal IRIS by addressing the following aims: 1) To identify the leukocyte subset(s) accounting for lethal cryptococcal IRIS; 2) To identify the cytokine(s) accounting for lethal cryptococcal IRIS; 3) To identify the factors regulating CD4+ T cells responses during cryptococcal IRIS. Successful completion of this study would gain novel insights into the cellular and molecular mechanisms that mediate lethal immune responses during cryptococcal IRIS and identify potential targets for treatment of HIV/AIDS-associated cryptococcal IRIS patients.

Up to $749K
2031-03-31
health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Mechanisms of Dynamic Cytoskeleton and Membrane Interactions

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NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY/ABSTRACT Dynamic interactions between intercellular membranes and the cortical cytoskeleton are critical for cell survival. During their normal functions, cells face physiological and environmental stresses that can lead to rupture of the plasma membrane and/or of the nuclear envelope. Rapid repair of such injuries, whether arising from daily activities or resulting from trauma, infection, or diseases such as cancer, is an active area of cell biology research. My lab has a long-standing track record in successfully identifying key molecules and elucidating their in vivo roles at the cell cortex necessary for the repair of plasma membrane and at the nuclear envelope necessary for repair of the nuclear cortex. The overall focus of the lab is to delineate how cells deal with such cell and/or nuclear cortex disruptions to efficiently and effectively repair the lesions. We have developed a robust inducible single cell repair model using the syncytial Drosophila embryo that has superb amenability for live imaging and genetic tractability that is unavailable in other cell wound repair models. We have also established a model for the newly appreciated nuclear export pathway (Nuclear Envelope budding) on the surface of Drosophila salivary gland and S2 cell nuclei that provides the same superb amenability for live imaging and genetic approaches. While both systems rely heavily on dynamic membrane and/or cytoskeleton/nucleoskeleton interactions, a major challenge in both of these systems is the absence of a molecular outline of the events occurring during the repair and/or export processes in any organism or system. Our goals during the proposed period are to establish the molecular framework underpinning these processes using a combination of state-of-the-art cell biological, genetic, developmental, biochemical, and high-resolution imaging approaches. Our studies are expected to be of significant medical relevance, as understanding the molecules, machineries, and pathways governing cell wound repair, NE-budding (nuclear export), and dynamic membrane-cytoskeleton/nucleoskeleton interactions will be extremely valuable for elucidating fundamental cellular mechanisms, as well as for developing new or enhancing existing strategies for treating conditions associated with cell/nuclear damage, and for disciplines such as regenerative medicine where cell based constructs are used to reconstruct tissues, clinical drug delivery systems where molecules cross cell membranes, and for virus nuclear egress.

Up to $614K
2031-02-28
health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Mechanisms of Micro-Nanoplastics Uptake, Translocation, and Toxicity in In Vitro Human Intestinal Models: Implications for Health and Inflammation

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NIEHS - National Institute of Environmental Health Sciences

PROJECT SUMMARY Micro-nano-plastics (MNPs) are small plastic particles resulting from the environmental breakdown of plastic waste over time. These particles have accumulated in ecosystems and entered the food web through contaminated water and food, trophic transfer, and exposure during food processing and packaging. Recent studies have detected MNPs in nearly every human organ and tissue, underscoring their widespread presence. While it is known that MNPs can cross biological barriers like the intestine, the health effects of MNP exposure are still poorly understood, and the mechanisms that allow MNPs to bypass these barriers remain unclear. Additionally, most toxicological studies have relied on simplified MNP models, such as polystyrene beads, which do not accurately reflect the complex physicochemical properties of real-world MNPs. This project aims to bridge these knowledge gaps by exploring the intestinal uptake mechanisms, biodistribution, and impacts on intestinal health of environmentally relevant MNPs. The focus will be on the effects of MNP polymer type, size, surface chemistry (including weathering), and prolonged exposure on MNP toxicity and inflammatory responses. Our central hypotheses are: (I) MNP properties such as size, polymer type, and environmental weathering influence their uptake, translocation, toxicity, and inflammatory effects; (II) MNPs are taken up through both passive diffusion and energy-dependent endocytosis pathways; (III) prolonged exposure enhances MNP uptake by altering gene expression related to cell junctions, endocytosis, and inflammation; and (IV) intestinal inflammation, such as in inflammatory bowel disease (IBD), increases MNP translocation by enhancing intestinal permeability, which further promotes biodistribution. To achieve these objectives, the study is organized into two specific aims: Aim 1: Synthesize and characterize environmentally relevant “tracer” MNPs (Au Core-Plastic Shell) for use in toxicological studies. These physicochemically characterized MNPs will be subjected to weathering/aging processes to simulate environmental conditions, and will enable MNP quantification using ICP-MS. The characterization will focus on the physicochemical properties of MNPs, including size, polymer type, and surface chemistry. Aim 2: Investigate MNP translocation mechanisms and toxicity using advanced in vitro models. This will include a triculture model of the small intestinal epithelium and human Intestine-on-Chip (IOC) models derived from both healthy and IBD donor organoids. Simulated digestion will replicate real-world exposure conditions, and the effects of MNPs on intestinal toxicity, gene expression, and inflammatory response will be examined. In addition to providing state of the art, transdisciplinary training to a doctoral student, the findings from this research will provide critical data for assessing the risks of MNP ingestion, inform regulatory actions, and open new research avenues in toxicology and epidemiology for this emerging environmental pollutant.

Up to $38K
2029-02-28
health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

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