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Community Foundation of St. Joseph County

Community Foundation of St. Joseph County ($200M in assets) supports nonprofits in IN through grants focused on education, community development, health, arts. Awards range from $1,000 to $50,000.

Community Foundation of Tampa Bay

Community Foundation of Tampa Bay ($500M in assets) supports nonprofits in FL through grants focused on education, health, arts, community development. Awards range from $2,500 to $150,000.

Community Foundation of the Dan River Region

Community Foundation of the Dan River Region ($50M in assets) supports nonprofits in VA through grants focused on education, community development, health, arts. Awards range from $1,000 to $25,000.

Community Foundation of the Fox River Valley

Community Foundation of the Fox River Valley ($100M in assets) supports nonprofits in IL through grants focused on education, community development, health, arts. Awards range from $1,000 to $25,000.

Community Foundation of the Lowcountry

Community Foundation of the Lowcountry ($150M in assets) supports nonprofits in SC through grants focused on education, community development, health, arts. Awards range from $1,000 to $50,000.

Community Foundation of the Ozarks

Community Foundation of the Ozarks ($500M in assets) supports nonprofits in AR through grants focused on education, community development, health, arts. Awards range from $2,000 to $100,000.

Community Foundation of the Ozarks

Community Foundation of the Ozarks ($500M in assets) supports nonprofits in MO through grants focused on education, community development, health, arts. Awards range from $1,000 to $75,000.

Community Foundation of Tompkins County

Community Foundation of Tompkins County ($50M in assets) supports nonprofits in NY through grants focused on education, environment, arts, community development. Awards range from $1,000 to $25,000.

Community Foundation of Utah

Community Foundation of Utah ($250M in assets) supports nonprofits in UT through grants focused on education, community development, health, arts. Awards range from $1,000 to $75,000.

Community Foundation of Western Massachusetts

Community Foundation of Western Massachusetts ($200M in assets) supports nonprofits in MA through grants focused on education, community development, health, arts. Awards range from $2,000 to $75,000.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY/ABSTRACT Significant gaps in care exist in addressing the intersection of HIV and substance use disorder (SUD) treatment. Despite pharmacists providing evidence-based services for HIV prevention and harm reduction, their potential to reach those with co-occurring HIV and SUD has not been fully realized. Dr. Tarfa, a pharmacist and PhD-trained health services researcher at Yale School of Medicine, is uniquely positioned to adapt and implement an integrated training and service provision program in community pharmacies. Dr. Tarfa’s early work showed that people with HIV are receptive to HIV/SUD care in pharmacies, and community pharmacists are willing to provide this care. The strong mentorship team of this K99/R00 will shape her into an independent investigator by supporting her in all aspects of the project. The team includes Dr. Springer, MD (HIV and addiction medicine), Dr. Rabin, PhD, MPH, PharmD (implementation science), Dr. Carpenter, PhD, MSPH (pharmacy workflow and quantitative methods), and Dr. Opara, PhD, LMSW, MPH (co-design), to leverage all stages of the project. During the K99 phase of this project, with the support of her mentorship team, Dr. Tarfa will receive training in addiction medicine, survey methodology, pharmacy service delivery workflow, co-design participatory research, and implementation science. These trainings will directly support the K99 activities to conduct: (1) a community pharmacy assessment to identify implementation determinants, current HIV/SUD service provision, and readiness for integrated care through a state-wide survey as well as focus groups with pharmacists and people with lived experience of HIV and/or SUD; and (2) utilize Community Engagement Studios for intervention adaptation/co-design including people with lived experience, pharmacists, and clinicians, to refine implementation strategies. The R00 phase will pilot the intervention and evaluate the feasibility, acceptability, and early implementation outcomes using PRISM and RE-AIM frameworks. Service uptake (HIV testing, PrEP initiation, ART provision, SUD screening, naloxone dispensing) and post- implementation interviews with pharmacy staff and service users will assess implementation outcomes and inform further refinement. This K99/R00 aligns with three of NIDA’s five strategic priorities by advancing novel prevention, treatment, and harm reduction strategies; accelerating research at the HIV-SUD intersection; and enhancing real-world implementation of community pharmacies care. The successful completion of this K99/R00 will prepare Dr. Tarfa to become an independent investigator, pioneering and evaluating pharmacy- based interventions that integrate HIV and SUD care. This will lay a strong foundation for future R01-funded research that will drive lasting change in the field.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY Advancements in antiretroviral therapy (ART) have significantly increased the life expectancy of people with HIV (PWH). However, this extended longevity has brought about a heightened risk of cardiovascular disease (CVD). Notably, women with HIV (WWH) seem to face a disproportionately elevated risk of thrombotic adverse events, such as acute myocardial infarction (MI). Our group has reported significantly greater thrombogenicity in PWH using an ex vivo thrombosis model, with particularly marked findings among WWH, confirming the existence of sex-based differences in the underlying pathobiology. Although the precise mechanisms contributing to this greater increase in thrombogenic risk among WWH are not fully understood, certain key factors are emerging: (a) Generalized immune activation in HIV-1 infection strongly predicts the progression of both HIV and its comorbidities, including CVD. Women, in particular, exhibit a robust immune response and a higher risk of progressing to AIDS than men. Toll-like receptors (TLRs), crucial components of the innate immune system for their ability to recognize and respond to pathogens, including viruses, are influenced by estrogen levels and known to modulate platelet reactivity; (b) Platelets, the second most abundant blood cell type, play a crucial role in atherothrombosis and inflammation. Enhanced platelet reactivity is known to elevate the risk of CV events and has been reported in PWH. Additionally, platelets have been shown to express all 10 TLRs; (c) Age-related changes in sex-hormones affect the rates of CVD in women. Estrogens regulate vascular reactivity, blood pressure, endothelial function and also affect the immune system, and decrease in estrogen levels post menopause adversely affect traditional CV risk factors. Data suggest that WWH experience earlier menopause and more menopausal symptoms and age-related comorbidities compared to women without HIV. Drawing from these key elements, we have formulated the hypothesis that HIV primes platelets increasing their responsiveness to TLR4 and TLR7 stimulation, and changes across the menopausal transition alter TLR-driven platelet activation and thrombogenicity in WWH through estrogen. The goal of this project is to define how HIV and reproductive aging interact to increase thrombotic risk in women with HIV, using functional thrombogenic assays integrated with exploratory molecular profiling to gain mechanistic insight. These initiatives are geared towards improving strategies for preventing and managing thrombotic events in this vulnerable population, ultimately enhancing patient outcomes and quality of life.

NIMH - National Institute of Mental Health

PROJECT SUMMARY / ABSTRACT Despite gains in men’s engagement in HIV testing, prevention, and treatment in sub-Saharan Africa (SSA), men are still less likely than women to test for HIV, less likely to start antiretroviral treatment (ART) and pre-exposure prophylaxis (PrEP), and more likely to default from care and have virological failure. Highly mobile Lake Victoria fishermen in Kenya are at high risk of HIV acquisition due to their mobility and a transactional sex economy embedded within the fish trade. Fishermen have difficulty accessing services during typical clinic hours, and HIV-related stigma and gender norms that run counter to men’s healthcare- seeking also limit their uptake of HIV testing, prevention and treatment. Our recently completed social network-based, HIV status-neutral intervention (“Owete”) significantly increased HIV testing and linkage for ART or PrEP among Kenyan fishermen. HIV self-testing was higher in intervention network clusters (60% vs. 10%, p<0.001), as was linkage to health facilities among those who tested (67% vs. 16%, p<0.001). In Owete we identified close social networks of men and trained socially connected men in networks to act as “Promoters” of HIV testing, prevention and treatment. Promoters distributed HIV self-test kits and a small (KSh500, $4) transport voucher redeemable at linkage to health facilities to men in their networks. Promoters were trained to encourage peers to test and link to either PrEP or ART. We have engaged the Kenya Ministry of Health to now address how the Owete intervention can best be deployed at scale to proceed with wide-scale implementation of the intervention. Challenges to wider-scale implementation of Owete in Kenya are: costs and complexity of full social network surveys and promoter selection, and a limited evidence base for the amount and use of vouchers as an incentive to link to care. We will use the Multiphase Optimization Strategy (MOST) to identify an effective, scalable, and cost- effective version of Owete. In the MOST Preparation Phase, we will Identify scalable options for selection of network central Promoters and incentive levels (Aim 1). We will: use existing data from Owete and modeling to identify candidate components, set optimization criterion, and pilot-test candidate components in one beach. In the MOST Optimization Phase, we will comparatively test Promoter selection strategies, voucher effects, examine mechanisms of intervention action (Aim 2). In a 2x3 factorial trial, we will assess HIV self-testing and linkage outcomes at 3 and 6 months in 6 beaches, and use mixed methods to identify pathways of intervention action. We will estimate the incremental cost-effectiveness of candidate intervention combinations (Aim 3), employing time-driven activity-based costing and Markov modeling to assess cost-effectiveness; and use optimization criteria to identify the most effective, feasible, and cost- effective combination of Promoter selection strategy and incentive level for scale-up. Impact: This research will result in a scalable approach to engaging mobile men in HIV testing and care to reduce HIV in Africa.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY/ABSTRACT This proposal will evaluate the comparative effectiveness of advanced therapies (biologics and small molecules) used to treat pediatric Crohn’s Disease using innovative pharmacoepidemiologic methods. Crohn’s Disease, a type of inflammatory bowel disease (IBD), affects over 50,000 children in the U.S. and, when poorly controlled, can lead to pain, fatigue, growth failure, and irreversible surgery. While more than 10 advanced therapies are FDA-approved for adults with Crohn’s Disease, only two—both anti-tumor necrosis factor (Anti- TNF) biologics—are approved for children. This approval gap influences treatment choice, as children with Crohn’s Disease are typically treated initially with FDA-approved anti-TNFs, prior to mechanistically-diverse off- label therapies, despite growing adult data suggesting comparable or even superior safety and effectiveness of alternative agents. These treatment decisions are often influenced by insurers requiring failure of FDA- approved anti-TNFs prior to prescription of second-line off-label therapies, confounding direct comparisons. Innovative risk adjustment methods are needed to overcome these barriers to inform treatment selection and match the right medication to each patient’s unique type of Crohn’s Disease. In Aim 1, Dr. Constant will compare the clinical effectiveness of anti-TNFs and anti-interleukin biologics, an emerging medication class with comparable effectiveness to anti-TNFs in adult studies. Analyses will leverage a validated multicenter retrospective cohort of pediatric patients with Crohn’s Disease to power state-of-the-art causal inference methods which account for demographic and disease-related confounders influencing treatment choice. In Aim 2, he will validate and expand upon these findings through a prospective observational cohort study incorporating patient-reported outcomes to capture a comprehensive view of comparative effectiveness. In Aim 3, he will pilot a pragmatic randomized clinical trial comparing two off-label advanced therapies (risankizumab and upadacitinib) among children with anti-TNF-refractory Crohn’s Disease. This aim will assess the feasibility of comparing off-label therapies within a pragmatic trial structure, allowing for evolving real-world treatment strategies including dose escalation, across a broadly inclusive pediatric Crohn’s Disease population. This research and training plan is supported by a complementary multidisciplinary mentorship team, led by co- primary mentors and nationally recognized pharmacoepidemiologists Dr. James Feinstein and Dr. Frank Scott. Content mentors with aim-specific expertise include Dr. Debashis Ghosh (Aim 1: causal inference), Dr. Lindsey Albenberg (Aim 2: prospective observational research and patient-reported outcomes), and Dr. Calies Menard- Katcher (Aim 3: innovative clinical trial design). This work will advance real-world evidence to inform therapy selection for children with Crohn’s Disease and lay the foundation for future R01-level multicenter pragmatic randomized trials to definitively compare therapies under real-world conditions, launching Dr. Constant’s career as an independent investigator and leader in pediatric IBD comparative effectiveness research.

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY The Duke University Program in Computational Biology and Bioinformatics (CBB) is a predoctoral training program with a 20-year track-record of training graduate students at the interdisciplinary intersection of the quantitative and biomedical sciences. CBB is a degree-granting program typically composed of 30–40 students and drawing on approximately 750 faculty from departments across the Schools of Medicine, Engineering, and Arts & Sciences. CBB provides rigorous training in quantitative approaches from computer science, statistics, mathematics, physics, and engineering to enable its students to successfully address challenges in applications to biomedical science. CBB students engage in cutting edge research, developing and applying novel quantitative methods to a broad range of questions in genomics, structural biology, molecular and evolutionary genetics, medical data science, systems biology, microbiome studies, cancer biology and immunology. As a means of fostering excellence in research, CBB students 1) work independently and collaboratively as part of a team, 2) conduct research responsibly, with a commitment to data sharing and reproducible analysis, 3) effectively communicate science to a broad range of audiences, 4) teach in formal and informal settings, and 5) develop professional and leadership skills in preparation for individualized career paths. The training program incorporates foundational courses in statistics, computer science and molecular biology, with enough time built into the program to allow students with diverse research and academic experience to achieve early proficiency in these areas through additional training. The breadth of research areas and potential dissertation research projects are explored through at least 3 rotations performed in CBB faculty labs, along with seminars, journal clubs and an annual off-site research retreat. The training program also includes required courses in Responsible Conduct of Research and Reproducible Research, with participation by both students and faculty. Career development activities are designed to address success as a beginning graduate student and then develop skills and tools to be a successful professional. With this powerful combination of skills, CBB alumni are in high demand, choosing career paths spanning academic research and teaching; industrial research from startups to big pharma and tech; and government institutes. The statistics summarizing our program over the past 5 years provide evidence for a successful training program, timely graduation (average 5.7 years to PhD), successful placement (100% of graduates working in academics, government or industry) and excellent training outcomes (avg. 2.7 publications per student). This training grant will provide funding for the first two years for three students with deficiencies in one of the cores, CBB disciplines, and will allow them extra training time to deepen skills relevant to their dissertation research. This T32 program will allow the Duke’s CBB program to amplify the individualized intellectual and professional development of independent and creative young quantitative scientists.

NIGMS - National Institute of General Medical Sciences

Project Summary Structural variants (SVs) are complex genetic rearrangements of medium to large size (>50 bp) that overall impact more base-pairs of the genome than any other type of genetic variants. These variants are implicated in many diseases, such as neurodevelopmental disorders (NDDs) and cancers. However, our understanding of their contribution to complex diseases remains incomplete. The large-scale studies have mostly focused on non-repetitive regions of genome and coding segments, overlooking potentially relevant areas outside these regions. These limitations are the result of lack of ability to accurately predict and genotype SVs in complex and repetitive regions of the genome, and the complexity of interpreting the functional impact of non-coding SVs. One of the primary objectives of my research is to study the hidden contribution of SVs to complex disorders by addressing these and other shortcomings in our current analysis. Despite the recent advances in computational methods using whole-genome sequencing (WGS) data, accurately predicting and genotyping SVs in repetitive regions of the genome, such as segmental duplications, remains challenging. Even with long-read WGS data, state-of-the-art SV callers are still unable to detect a significant fraction of the SVs in these hard-to-call regions, as demonstrated by the analysis of T2T-CHM13 data. Approximately 15% of the genome comprises regions that are difficult to accurately call variants, and our analysis of the T2T-CHM13 and HG002 assemblies suggests that these regions contain a significant high proportion of SVs. In addition, studying SVs in diseases also requires specialized novel methods, for accurate detection of de novo or somatic SVs. Development of these methods will open the door for comprehensive study of the contribution of SVs in hard-to-call genomic regions to complex disorders. Another major limitation of current studies of SVs in complex disorders is due to challenges in our ability to interpret non-coding SVs. It is hypothesized that non-coding SVs can contribute to complex disorders through a variety of mechanisms. One major such mechanism is the ability of non-coding SVs to disrupt transcriptional regulation. For example, this can occur through changes in the 3D genome architecture, which subsequently modify enhancer-gene interactions and result in ectopic gene expression. Thus, there is a need for development of accurate methods for predicting the impact of non-coding SVs on transcriptional regulation and cell-type specific gene-enhancer interactions. Finally, development of these tools will result in much needed comprehensive investigation of non-coding SVs observed in large-scale complex disorder studies for their impact on transcriptional regulation landscape, 3D genome structure and enhancer-gene interaction. The overall objectives of this proposal are as follows: 1. Dissecting contribution of SVs in hard-to-call genomic regions to complex disorders: Our first objective focuses on deciphering the role of SVs in previously inaccessible and hard-to-call regions of the genome. We will develop innovative methods to enhance the detection and genotyping of SVs, including both de novo and somatic variants, in these regions. We will also leverage these tools to construct a comprehensive catalog of SVs in these regions, utilizing an expanding collection of long-read WGS data from both normal and disease samples. Finally, we will quantify and explore the contribution of SVs in these regions to complex disorders, including autism and cancer. 2. Studying the role of non-coding SVs in complex disorders: Our second objective is to study impact of non-coding SVs to complex disorders. It is hypothesized that certain non-coding SVs can contribute to complex disorders by reshaping the gene regulation landscape. This can involve disrupting 3D genome architecture, altering gene-enhancer interactions, and driving ectopic gene expression. As part of this project we will develop methods to predict the impact of non-coding SVs on the gene-enhancer interactions landscape. We will utilize these methods to study the contribution of non-coding SVs through such a mechanism on complex disorders. In the next five years, my lab's overarching goal is to enhance our understanding of the role of SVs in human diseases and health. The results of this research will expand our understanding of the contribution of SVs to complex disorders, help discovery of novel disease biomarkers, reduce the missing heritability gap in complex disorders, and even discover potential novel drug targets that have been ignored till now.

NIGMS - National Institute of General Medical Sciences

Summary Biological size control is of broad importance to all processes of life. Among cytoskeletal assemblies, proper chromosome segregation depends on regulated, stable length of the metaphase spindle and elongation in anaphase B. While the interplay of force and biochemical regulation is central to understanding the spindle, our understanding of this interplay is limited. As a result, we still lack a predictive theory of spindle regulation. One notable knowledge gap is the role of the nuclear envelope in closed mitosis, wherein the spindle segregates chromosomes within the intact nucleus. Nuclear envelope remodeling is essential for proper chro- mosome segregation, and increasing evidence suggests that the envelope can exert significant force on the spindle. However, we currently do not know what sets the magnitude of this force, nor nuclear envelope con- tributions to spindle regulation. Our recent model implementation has opened up simulation of spindle-nuclear envelope coupling, enabling the proposed project. The central objective of this study is to determine the inter- play between force and biochemistry responsible for regulated spindle length, stability, and elongation in closed mitosis. Aim 1: Identify the mechanisms by which force and biochemistry regulate the metaphase spindle. Aim 2: Determine the mechanisms by which force and biochemistry regulate spindle elongation. This project is significant because it will identify new principles of spindle regulation, using a minimal, geneti- cally tractable system to uncover conserved physical principles of cytoskeleton-nucleus coupling. The results will advance understanding of how physical and molecular constraints shape cytoskeletal assemblies. Insights from this project will inform related research on organelle remodeling, shape sensing, and compartmentaliza- tion. It will also develop cutting-edge modeling tools for the cytoskeleton and nuclear envelope. This project is innovative because while spindle regulation has been studied previously, we will test novel idea that the nuclear envelope and spindle mechanical interactions are important for spindle regulation in closed mitosis. In addition, we will elucidate the mechanisms of spindle stability, healing, and response to envelope force, which have seen little previous study. The project will develop state-of-the-art computational models of spindle regulation, create new fission-yeast spindle and NE mutants and protocols for spindle perturbation, and integrate multiple advanced assays to perturb and quantify spindle dynamics. This project will elucidate the sensing of and feedback between biochemistry and spindle-generated and nuclear envelope forces. Mitotic spindle defects can lead to chromosome missegregation and genome instability, con- tributing to cancer, developmental disorders, and degenerative disease. Mutations that alter nuclear envelope morphology are associated with disease states such as muscular dystrophy, and disruption of nuclear integrity can cause DNA damage and is also associated with cancer. This project will add to our understanding of the underlying cellular mechanisms contributing to these health conditions.

NIGMS - National Institute of General Medical Sciences

Project Summary Cells adapt to their surrounding environments by forming dynamic contact with each other. These contacts are maintained by molecular interactions between receptors and ligands on cell surfaces. The immunoglobulin (Ig) fold, as the largest and most typical class of domains for cell surface recognition, is widely distributed in almost all types of cell surface receptors and their corresponding ligands. Some Ig domains can interact with multiple targets with various binding affinities. The difference in binding specificity of these proteins is a crucial determinant of their biological functions. Moreover, a majority of cell surface proteins contain multiple Ig domains in their extracellular regions. Not all of these domains are directly involved in binding partner recognition. To understand the function of cell surface proteins, it is necessary to determine which specific domains are responsible for binding, how Ig domain binding selectivity is determined, and why multiple extracellular domains need to be evolved. However, it is currently highly challenging to measure the extracellular interactions between cell surface proteins on a systematic level. These interactions are difficult to detect by standard biochemical assays due to the transient nature of their binding kinetics. Computational modeling can reach dimensions that are currently unapproachable in the laboratory. Unfortunately, even the state-of-the-art deep-learning-based methods, such as AlphaFold 3, are not sensitive enough to model the transient interactions among cell surface proteins. Thus, the objective of this proposal is to develop new methods that can be used to predict and simulate the specific interactions between cell surface proteins with Ig domains. We have constructed a non-redundant structural database for Ig domain interactions. Using this database, we will first develop a computational platform that combine protein language model and attention-based deep-learning model to identify potential new interactions between cell surface proteins. Moreover, we will generate a short list of domain pairs between two multi-domain cell surface proteins that are highly likely to mediate their interaction, therefore greatly reducing the complexity of experimental tests. We will further design a two-stage machine-learning strategy to predict the binding constants between specific Ig domains. We will use this method to understand why specific Ig domains can bind to multiple ligands with various affinities. Finally, we will propose a multiscale framework by incorporating protein conformational fluctuations estimated from molecular dynamics simulations into a new mesoscale model. We will use the multiscale framework to explore how multiple Ig domains regulate the intercellular interactions between cell surface proteins. All of our computational predictions will be experimentally validated by our long-term collaborators through an iterative process. Our long-term goal is to elucidate how interactions between cell surface proteins influence and regulate immune signaling and neural plasticity. Ultimately, the computational methods developed in this project are designed to be broadly applicable, enabling the study of protein interactions across diverse domain families beyond our primary systems of interest.

NCI - National Cancer Institute

PROJECT SUMMARY Drugs can be modified by human gut bacteria, leading to variability in efficacy and side-effects across people. Yet most of the ~19,000 FDA-approved drugs have not been tested for bacterial metabolism, and for those that have been screened, the responsible microbial enzymes are rarely known. Anti-cancer drugs epitomize this knowledge gap, with huge patient-to-patient variability and multiple documented links to specific bacterial strains and genes that alter drugs post-administration. This hinders our ability to design, prescribe, and dose cancer chemotherapies accurately and safely. A major roadblock is the immense diversity of microorganisms within a person’s gastrointestinal tract (the gut microbiota), including dynamic variability in enzyme presence/absence across strains of the same species, making it necessary to track causal genes not just taxa. Furthermore, state- of-the-art experimental screening approaches have insufficient scale to accommodate the rapidly growing list of drugs subject to gut bacterial metabolism. To remove these obstacles, we propose to develop a computational technology platform based on chemical and protein similarity that matches microbial enzymes with the drugs they are likely to modify. Supporting feasibility, our multi-PI team developed a prototype of this platform, called Similarity algorithms that Identify MicrobioMe Enzymatic Reactions (SIMMER). In the proposed project, we now aim to overcome three key limitations preventing the SIMMER prototype from being broadly applicable: the paucity of validated reactions for training and evaluation (Aim 1), variable performance across enzyme classes (Aim 2), and inability to query starting from a protein sequence rather than a chemical reaction (Aim 3). We will tackle these challenges by using large language models to incorporate protein structural similarity alongside sequence homology, linking traditionally siloed reaction-centric and sequence-based databases, and generating large-scale functional data to iteratively evaluate and improve SIMMER’s algorithms. The resulting tool will enable users to predict drugs that a given protein could modify and to prioritize gut microbial enzymes capable of performing known drug transformations. We have opted to focus on anti-cancer drugs as an initial proof-of-concept, given the rigorous prior literature implicating the microbiome in cancer therapy and the broad potential for translational impact. SIMMER 2.0 will speed up the discovery of chemotherapy-metabolizing enzymes, enabling focused work on specific drug classes and types of cancer. In addition, SIMMER predictions themselves will be useful for drug design and as inputs to personalized dosing algorithms. This cancer-focused project will be a key milestone towards a comprehensive map of all FDA-approved drugs and their microbial interactions. More broadly, the proposed methods will be easily extendable to other chemicals besides drugs, including diet- and host-derived small molecules.

NIGMS - National Institute of General Medical Sciences

Project Summary: Horseradish peroxidase (HRP) is a critical reporter enzyme widely used in diagnostics, and research tools due to its ability to amplify signal in assays like ELISAs, Western blots, and immunohistochemistry. However, current HRP reagents are largely derived from horseradish root, which results in heterogeneous mixtures of isoenzymes with varying glycosylation patterns, activity, and stability. This variability compromises reproducibility, complicates regulatory compliance, and presents significant manufacturing challenges. Moreover, recombinant HRP production has been historically hindered by its complex structural requirements, including the incorporation of a heme cofactor, multiple disulfide bonds, calcium ions, and glycosylation, which are difficult to replicate in microbial hosts. As a result, efforts to create a consistent, recombinant HRP alternative have proven unsuccessful, with current solutions like poly-HRP showing significant limitations in batch-to-batch consistency which is critical in high sensitivity assays. This SBIR Phase I project aims to overcome these challenges by using state-of-the-art computational protein design to develop a novel recombinant HRP mimetic that exhibits high stability, catalytically active properties, and scalability. Our approach involves two primary innovations: the design of a stable, de novo HRP enzyme that can be expressed efficiently in microbial systems, and the development of a self-assembling HRP nanoparticle that enables precise control of enzyme stoichiometry and enhances performance consistency. The proposed HRP mimetic will not only ensure high-quality production of HRP reagents but also enable genetic fusions with other functional domains, opening the door to more consistent and reliable diagnostic development. Our team has developed promising preliminary data indicating a highly de-risked application that will have a big impact. Our preliminary data demonstrate the feasibility of using computational protein design to create a de novo HRP that is easy to manufacture, and with this grant, we intend to transform it into a high-impact product with broad applications.

OD - NIH Office of the Director

Summary: The Lundquist Institute (TLI) is requesting funds to purchase a Leica STELLARIS confocal microscope to be housed in its established, centrally managed core facility. This new system is intended to replace an aging 12- year-old Leica SP8 microscope that no longer meets the evolving needs of our research community. A broad user group of 12 investigators (10 of whom are NIH-funded), who are all making significant and pioneering contributions to cross- disciplinary research at the interface between developmental biology, cell biology, molecular biology, cancer, endocrinology, neurobiology, immunology, and host-pathogen interactions, will immediately benefit from the transformative imaging capabilities of the instrument. The STELLARIS system offers major advancements in confocal imaging technology, including a tunable white light pulsed laser for fluorescence lifetime imaging microscopy (FLIM), integrated with the high-speed FALCON FLIM platform and capable of multiplexing up to 11 spectral channels. These features provide users with quantitative imaging modalities to monitor complex dynamic processes in live and fixed samples. The instrument also includes LIGHTNING super-resolution capabilities based on adaptive deconvolution, expanded spatial coverage, and Leica's proprietary HyD detectors with tunable spectral sensitivity (1-nm precision, 400–850 nm), enabling high- resolution, low-phototoxicity imaging across a wide range of fluorophores. Acquisition of this system will ensure continued access to state-of-the-art imaging technology, enabling investigators to generate high-quality, multidimensional datasets and address increasingly complex biological questions. This instrument will directly enhance the rigor, reproducibility, and competitiveness of NIH-supported research at TLI by facilitating transformative insights into molecular and cellular mechanisms of health and disease.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary/Abstract Germinal matrix-intraventricular hemorrhage (GM-IVH) is a significant neurological complication associated with high mortality rates and substantial neurodevelopmental disabilities. While the majority of GM-IVH cases are clinically asymptomatic, it is the most common cause of hydrocephalus in premature infants. Progressive cerebral ventricular dilation is an important diagnostic component of hydrocephalus and is typically identified through trans-fontanelle, cranial Ultrasound (CUS) in neonates. It is safe, cost-effective and can be conducted at the bedside with minimal disruption to the infant. However, current CUS clinical application is limited by numerous constraints, including: i) results are contingent upon the skills and experience of the ultrasonographer and radiologist Iii) limited access to the appropriate equipment and trained personnel in certain institutions due to prohibitive costs iii) due to the medical complexity of this vulnerable patient population, there is often a need to minimize stress, which can delay acquisition of important imaging when a patient is too unstable to undergo standard, often time consuming diagnostic US assessment. Within the last six years, conformable ultrasound electronics have been intensively investigated for imaging of many internal organs, however, to our knowledge, there are currently no studies on the feasibility of trans- fontanelle continuous ventricular ultrasound. Our goal is to investigate the monitoring of ventricular volume in neonates with GM-IVH using a wearable, adhesive ultrasound patch, and test the feasibility of simultaneous measurement of ventricular and sub-arachnoid size as well as cerebral blood flow. We hope this research will standardize interpretation, increase availability and reduce costs. Our work will introduce a novel patch design along with advanced piezoelectric transducers design, and a new image reconstruction method along with machine learning analysis of standard measurements such as ventricular index (VI), and anterior horn width (AHW), but also introduce AI based volumetric analysis. This work will be based on (1) novel patch design and advanced microfabrication of electronics (electronic science and engineering), (2) signal decoding for beamforming and image reconstruction (biomedical engineering and signal processing) and (3) clinical study on neonates and machine learning analysis (biomedical engineering and artificial intelligence). This study will provide the first in vivo validation of a conformable cranial ultrasound patch for neonatal brain monitoring with a significant advancement in neonatal monitoring, combining state-of-the-art piezoelectric sensor technology with advanced deep learning algorithms. We aim to demonstrate generalizability, robustness, and the potential to standardize CUS in this at-risk patient populations. This could ultimately reduce the incidence of severe neurodevelopmental impairment by providing uniform neurodiagnostic accuracy in a condition that is a major cause of mortality and neurodevelopmental impairment in this fragile population.

Conseil des arts et des lettres du Québec

CALQ supports artistic and literary creation in Quebec through grants to artists and organizations in all disciplines including theatre, dance, music, visual arts, literature, and film.

OD - NIH Office of the Director

Project summary/abstract Academic drug discovery centers (ADDCs) have emerged as a key resource and core facility for two distinct and interrelated pursuits: (1) the practice of chemical biology, with the discovery of chemical tools and probes to dissect biological mechanisms, and (2) the identification of small molecule ‘hits’ against molecular targets or cellular phenotypes as starting points for drug discovery. The Small Molecule Discovery Center at UCSF is one of the pioneering ADDCs and has deep expertise in diverse state-of-the-art hit-identification strategies, from biophysical fragment-based drug discovery (FBDD) to complex microscopy-based screens. Among the major advances in the industrialization of the drug discovery process over the past few decades is miniaturization of assay volume, from 96-well to 384-well to 1536-well plate formats. 1536-well plates incorporate assay volumes on the order of 2-microliters, offering much faster screening – leading to increased chemical diversity screened – as well as reduced consumption of precious or expensive assay components. One of the greatest challenges in running multi-step assays in 1536-well plates is the addition of liquids and their removal—usually by aspiration. The quality of liquid exchanges dramatically affects the performance of multi- component and multi-step screening assays. The development and commercialization of a centrifugation-based approach to liquid removal from 1536-well plates allows the running of high throughput cell-based and molecular- based drug screening assays. The Small Molecule Discovery Center at UCSF currently lacks the ability to evacuate the contents of 1536-well plates-which limits us to 384-well formats for assays requiring the evacuation and exchange of liquids. We are requesting a BlueWasher for our integrated robotic automation screening platform, which incorporates roboticized plate handling, liquid handing, automated incubation, and imaging systems for both biochemical- and cell-based assay formats. We are also requesting funds for an integrated robotic arm and plate hotels (BlueBench) to run multi-plate high throughput screens in batch mode. The increase in scale and efficiency that the incorporation of this equipment will provide to the Small Molecule Discovery Center core facility in moving from 384-well to 1536-well format will significantly increase the impact of Center’s work for UCSF PIs and project teams. Both the quantitative and qualitative aspects of increased the chemical diversity explored and the robustness and reproducibility of the assays will contribute to increased productivity for the Center in achieving its research services and shared-use goals.