Grants

Creative Justice

CWI: Youth Led Communications

Tri-City Joint Water and Sanitary Authority

Cyanotoxin Remediation Feasibility Study

North Seattle Family Center

An aging computer lab will be upgraded to provide low-income and limited English speakers with job readiness, ESL, life skills, and computer skills training through one-on-one technology tutoring and/or small group instruction.

DEPT OF DEFENSE.DEFENSE ADVANCED RESEARCH PROJECTS AGENCY (DARPA).DEF ADVANCED RESEARCH PROJECTS AGCY

Cyber Physical Systems Executing in Real Time (CyPhER Forge)

NSF

Louisiana State University (LSU) renews its thriving CyberCorps® Scholarship-for-Service (SFS) program that supports undergraduate and graduate students in computer science. LSU’s Department of Computer Science has experienced record-breaking growth since introducing of the CyberCorps® cybersecurity program in 2017. LSU is designated by the National Security Agency as a Center of Academic Excellence in Cyber Operations (CAE-CO) and offers SFS awardees a tightly integrated combination of applied cybersecurity experiences in the classroom and impactful research in state-of-the-art labs, addressing important problems in memory forensics, reverse engineering, malware analysis, Artificial Intelligence, network security, and more. LSU has established relationships with many federal and state partners to expose our students early to federal and state service. These include Cybersecurity and Infrastructure Security Agency (CISA), Idaho National Labs, Department of Homeland Security, the United States Secret Service, United States Army Cyber Command, the Cyber Crime Unit of the Louisiana State Police, and the Louisiana National Guard. All LSU SFS awardees participate in a federal or state cybersecurity-related internship program and perform focused cybersecurity research under the guidance of an LSU faculty member. Students also have the opportunity to study for and obtain cybersecurity certifications, attend cybersecurity-themed conferences, and become members of the LSU Cybersecurity Club, which offers cybersecurity activities such as Capture-the-flag (CTF) competitions and bootcamps focused on deep learning. The LSU SFS program also has significant benefits for society as a whole, as it substantially increases the number of highly trained cybersecurity professionals, a critical issue in defending our nation and its infrastructure. The scholarships help the LSU continue to recruit and retain excellent undergraduate and graduate cybersecurity students and provide resources for these exceptional students to pursue cybersecurity career. This project is supported by the CyberCorps® Scholarship for Service (SFS) program in the Division of Graduate Education, which funds proposals establishing or continuing scholarship programs in cybersecurity and aligns with the U.S. National Cyber Strategy to develop a superior cybersecurity workforce. Following graduation, scholarship recipients are required to work in cybersecurity for a federal, state, local, or tribal government organization for the same duration as their scholarship support. This project is jointly funded by the CyberCorps® Scholarship for Service (SFS) program and the Established Program to Stimulate Competitive Research (EPSCoR). This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

U.S. National Science Foundation

Cyberinfrastructure for Public Access and Open Science

NSF

This project aims to serve the national interest by producing more qualified technicians to meet workforce demands in cybersecurity. Keeping computers and information systems secure is a critical need and a major challenge in business, industry, and government. The growth of cyber-threats has created a need for many more workers who have the knowledge and skills to protect both existing and emerging technologies. In this project, the investigators aim to address the shortage of cybersecurity professionals by equipping high school and community college career counselors, academic advisers, and educators with the knowledge and resources needed to confidently guide students into cybersecurity careers. The investigators will develop materials and associated training that will reflect industry needs and present cybersecurity as a multidisciplinary field. While designed for formal advisers and counselors, the resources will also be distributed to informal advisers such as teachers, parents, and organizations that play a vital role in influencing students' career decisions. By providing those key influencers with relevant information, the project will expand awareness of cybersecurity career opportunities, making them more accessible to students. Looking beyond cybersecurity, this effort should serve as a model for expanding awareness and access to other high-demand technical fields and should advance the understanding of effective career guidance strategies. Cybersecurity encompasses dozens of distinct work roles (as defined in the NICE Workforce Framework for Cybersecurity, https://www.nist.gov/nice/framework), ranging from technical roles such as penetration testing to multidisciplinary roles such as policy analysis and governance, risk, and compliance. A major barrier in addressing the cybersecurity workforce gap is a lack of understanding of the wide range of work roles that the field offers and the skills that the various jobs entail. While many colleges and universities have developed robust cybersecurity curricula, there are limited resources and training available for career counselors, academic advisers, and educators to help them confidently guide students into cybersecurity career pathways. In this project, the investigators will pursue four objectives: (1) Develop a Cybersecurity Career Awareness Toolkit for counselors, advisers, and educators; a workbook for students; and informational materials for parents and organizations. (2) Design and deliver professional development workshops to inform high school and community college counselors, advisers, and educators about cybersecurity career pathways, academic programs of study, and use of the Toolkit. (3) Establish a Community of Practice among participants to facilitate ongoing collaboration, knowledge sharing, and support in guiding students through cybersecurity career pathways and academic programs. (4) Enhance cybersecurity career awareness among students through comprehensive outreach, resources, and partnerships with a variety of institutions. This project is funded by the Advanced Technological Education program, which focuses on the education of technicians for the advanced-technology fields that drive the nation's economy. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

U.S. National Science Foundation

Cybersecurity Innovation for Cyberinfrastructure

NSF

According to the Cybersecurity and Infrastructure Security Agency (CISA) Strategic Plan (2023), the United States faces a lack of both qualified and diverse cyber professionals. Compounding these concerns, the US Bureau of Labor Statistics (2024), projects a 32% increase in cyber-related careers from 2022-2032, resulting in nearly 17,000 job openings annually. To address this need, this project will establish a one-year Dual Enrollment (DE) pathway for high school students to earn a Technical Certificate of Credit (TCC) in Cybersecurity Fundamentals. Over three years, 135 students will be recruited into the program, gaining hands-on experiential learning through collaboration with local school systems and industry partners. The project aims to improve the transition from K-12 to higher education and careers, improving student readiness in this high-demand field. GPTC will structure the TCC as a two-semester program, integrating real-world simulations, professional interactions, and cybersecurity career exposure. Students will earn 18 college credits, developing foundational skills in network security, risk management, and digital forensics. The program culminates in a Student Showcase, where students present their skills to peers, faculty, and industry professionals. These activities will further strengthen the K-12 pipeline by establishing a pathway into for future enrollment into the college's cybersecurity program and other emerging technology fields, as well as an entry point into the workforce in a critical and high-demand field. This project is funded by the Advanced Technological Education program that focuses on the education of technicians for the advanced-technology fields that drive the nation's economy. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF

This project aims to serve the national interest by producing more qualified technicians to meet workforce demands in cybersecurity. Keeping computers and information systems secure is a critical need and a major challenge in business, industry, and government. The growth of cyber-threats has created a need for many more workers who have the knowledge and skills to protect both existing and emerging technologies. In this project, the investigators will enhance the college's cybersecurity program, with a focus on industry needs that have emerged in healthcare informatics and Governance, Risk, and Compliance (GRC). Specifically, the investigators aim to develop an Associate of Applied Science (AAS) degree program in cybersecurity and to incorporate new courses that will prepare students for employment as cybersecurity professionals in the large healthcare industry in Maryland, as well as in other industries that require knowledge of cybersecurity GRC. The curriculum will be designed to be accessible to cybersecurity students as well as students with concentrations in allied health and business. The project includes significant professional development in healthcare informatics and GRC for the faculty members who are developing the program. The new program will support local industries that have documented demand for cybersecurity practitioners. With respect to healthcare informatics, the region has a large number of healthcare organizations, including the Johns Hopkins Medical System as well as a hospital and medical campus adjacent to the Howard Community College campus. The new AAS program will be designed to replace the college's Associate of Arts (AA) degree in cybersecurity and to give students more workforce-ready skills. The new healthcare informatics course will emphasize the integration of information technology, cybersecurity, and healthcare systems. It will cover principles of cybersecurity; cloud computing; electronic health records; legal and ethical issues, including compliance with the Health Insurance Portability and Accountability Act (HIPAA); and the emerging role of artificial intelligence and data management tools. The course will incorporate hands-on exercises based on collaboration with industry practitioners, and it will use the college's Cyber Ready Clinic to give students firsthand experience working with small businesses in the medical field. The new GRC course will cover relevant laws and regulations, frameworks used to integrate security and privacy within organizational objectives, and the development and assessment of strategies for GRC implementation in different organizations. The course will aim to prepare students to work in organizations that must comply with specific GRC frameworks, and the content will align with relevant industry certifications. This project is funded by the Advanced Technological Education program, which focuses on the education of technicians for the advanced-technology fields that drive the nation's economy. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF

This project addresses a critical national need for enhanced training in computational methods that support the design of advanced materials for applications in solar energy, quantum computing, sensing, and optoelectronics. The processes that determine materials’ performance—such as excitation energy and charge transfer, nonradiative relaxation of excited electronic states, photoinduced isomerization and reactions—are governed by an interplay of electrons and nuclei. The understanding of this interplay requires specialized simulations of coupled electronic and nuclear dynamics. However, researchers often lack specialized high-quality training in these complex methods as well as practical experience with the advanced software tools that implement them. This project meets that need by offering intensive training through four summer schools focused on the cyberinfrastructure (CI) for nonadiabatic quantum dynamics (NAQD) simulations and their integration with machine learning (ML) tools and excited-state electronic structure calculations. Online educational materials and a new university course will expand the project’s reach, helping to equip students and researchers across the country with the skills to use the cutting-edge computational tools for accurate modeling of broad range of quantum dynamics phenomena in complex systems. By building a stronger and better-prepared scientific workforce, by broadening participation, and by facilitating the adoption of the advanced CI for NAQD and ML, this project promotes the progress in material science, supports technological innovation and education, and enhances societal impacts and national prosperity. This implementation project will build capacity within the scientific community working on quantum-classical and quantum modeling of nonadiabatic dynamics in materials. It will do so by providing conceptual and hands-on training to approximately 100 graduate students, postdoctoral researchers, and early-career scientists through a series of four summer schools. The events will focus on advanced software packages that support NAQD, excited-state electronic structure calculations, and the application of machine learning to these problems. Sessions will be taught by leading experts, including original developers of more than 30 specialized tools and libraries. Online tutorials, input examples, and documentation will be created to promote broader adoption of these tools. The project will also contribute new educational content by developing and incorporating a "Machine Learning for Chemists" course into the undergraduate and graduate curriculum at the University at Buffalo. Additionally, the PI will develop workflows and tutorials for the comprehensive and modular Libra software package to facilitate integrated NAQD simulations. Overall, the project aims to bridge critical training gaps, advance computational capabilities, and catalyze the use of modern CI tools in chemical and materials research. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF

This BRIDGE-QC training project addresses the nationwide shortage of professionals in Quantum Information Science (QIS) and the limited regional presence in this rapidly emerging field. QIS is advancing quickly, with transformative applications in sensing, computing, and networking. However, the United States faces a critical workforce gap in QIS and has called for intensified efforts to attract, educate, and develop a robust quantum workforce. Despite these national efforts, the educational infrastructure and research ecosystem needed to train quantum scientists remain nascent. BRIDGE-QC aims to meet the national demand for a quantum-ready workforce while also expanding opportunities in the field. BRIDGE-QC has two primary goals: (1) to develop a highly skilled quantum computing workforce by training students as quantum users, researchers, and contributors; and (2) to build and sustain a talent pipeline. The project takes a hands-on, interdisciplinary, and collaborative approach, creating a dynamic learning environment that combines formal coursework with informal, student-driven experiences. Core activities include new course development: Introduction to Quantum Computing and Quantum Algorithms and Applications, and the establishment of a quantum computing minor open to students across disciplines. To foster early engagement, BRIDGE-QC recruits high-achieving sophomores and juniors through Clemson's Creative Inquiry program and the Undergraduate Research Experience, and supports student-led initiatives such as the Quantum Club and Quantathons to promote community and partnerships with industry and research institutions. The project will deliver a comprehensive set of educational materials, including lecture notes, labs, onboarding modules, tutorials, source code, and scholarly publications. These resources will be publicly accessible and disseminated to support broad adoption at the state, regional, and national levels. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Oregon Business Development Department

Cycle Dog

NYC Department of Cultural Affairs

CYPRECO of America, Inc.

Cypress Education Foundation

Cypress Education Foundation is an active grantmaking foundation based in Cypress, CA. Focus: education. Contact the foundation directly for current funding opportunities.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary Multiple Sclerosis (MS) is a debilitating autoimmune disease wherein activated immune cells mistakenly attack the protective myelin coating on neurons. This results in scarring and the formation of lesions in the brain and/or spinal cord that contribute to a host of symptoms that vary dependent on the location of the injury. The precise etiology of MS remains unknown, though recent studies have pointed towards a combination of genetic and environmental factors. Intriguingly, a strong correlation exists between previous exposure to Ebstein-Barr virus, which increases the risk of developing MS by 30-fold. As this highlights a potentially important role that viral infection may play in the initiation of MS, our lab utilizes a murine neurotropic JHM strain of mouse hepatitis virus (JHMV) that results in an acute encephalomyelitis that is accompanied by gray matter involvement with infection of oligodendrocytes, astrocytes, and microglia. JHMV persists in the white matter tracts of the spinal cord, inducing demyelination resulting in hind-limb paralysis in mice. We and others have demonstrated previously that microglia, a resident innate immune cell population that resides in the central nervous system (CNS), are critical in constraining the immune response in demyelinating models of MS. Intriguingly, in areas of demyelination undergoing remyelination, there is a significant upregulation of cystatin F (Cst7), a protease inhibitor. While Cst7 is expressed on many immune cells, we’ve shown that microglia are the predominant source of Cst7 in the brain. Thus, this proposal seeks to define the role of microglia-derived Cst7 in the context of a viral infection with JHMV. We propose to infect novel transgenic conditional knockout mice for Cst7 on microglia and wild-type animals with JHMV to determine the impact of Cst7 on the immune response. A combination of flow cytometry and imaging modalities will be utilized to characterize differences in brain immune cell infiltration and activation. The impact of the conditional ablation of Cst7 on demyelination and subsequent remyelination will be assessed as well, using state-of-the-art techniques like spatial transcriptomics (Aim 1). Based on our preliminary and published findings, we hypothesize that Cst7 expressed on microglia is host protective. Therefore, we also propose to evaluate Cst7 as a potential therapeutic for demyelinating diseases by employing an overexpression model. Cst7 will be overexpressed in microglia in mice infected with JHMV and the subsequent immune response and myelination status will be evaluated using similar techniques as described above (Aim 2). Together, these aims seek to evaluate the role of microglia-derived Cst7 in an effort to further delineate mechanisms of demyelination and remyelination. As it is extremely rare for damaged neurons to undergo remyelination in MS, defining these mechanisms further will provide invaluable insight for the advancement of new therapeutics.

Cystic Fibrosis Canada

Funds CF research to improve treatments and find a cure for cystic fibrosis. Supports basic, clinical, and translational research.

NCI - National Cancer Institute

ABSTRACT: Up to 75% of patients diagnosed with high-grade, non-muscle-invasive bladder cancer (BC) will develop recurrences. Left undetected or untreated, recurrent bladder cancer leads to muscle invasion and radical cystectomy, a major surgery with high morbidity and mortality. Thus, clinical guidelines recommend surveillance every 3–12 months, making BC the costliest cancer to treat over a patient’s lifetime. The standard- of-care tool for BC surveillance, in-office white light cystoscopy (WLC), has low sensitivity and specificity for the leading cause of recurrence: urothelial carcinoma in situ (CIS). The most promising technique to improve the sensitivity of CIS detection, blue light cystoscopy (BLC), has low clinical adoption because it is costly, time- consuming, and has low specificity for CIS. Our long-term goal is to improve the detection of CIS during in- office surveillance. The main objective of this proposal is to develop a multimodal tool with high sensitivity and specificity for CIS that is appropriate for in-office surveillance: real-time digitally stained WLC (dsWLC)–guided polarization-sensitive optical coherence tomography (PS-OCT). Digital staining uses deep learning to convert WLC images into accurate, low-cost, BLC look-alikes. PS-OCT is a microscopic imaging technique proven to improve the specificity of BLC. Our preliminary data and published literature confirm that PS-OCT has the specificity to differentiate CIS from inflammation, a primary contributor to false positives in WLC and BLC that leads to unnecessary biopsies and associated co-morbidities. The proposed two-prong strategy of dsWLC and PS-OCT will thus bring the benefits of BLC (high sensitivity) to the office while 1) removing the administrative burdens that prevent its widespread adoption and 2) adding the specificity that it lacks. Our central hypothesis is that dsWLC-guided PS-OCT has better sensitivity of detection for CIS than the standard of care for in-office surveillance (WLC), comparable sensitivity to BLC, and better specificity than both. Our specific aims are: 1) Improve the sensitivity of in-office CIS detection by developing dsWLC, 2) Improve the specificity of in-office CIS detection by building a miniature PS-OCT probe, and 3) Demonstrate the clinical effectiveness of real-time dsWLC+PS-OCT for bladder cancer detection. Aim 1 will build on our expertise in machine learning and our preliminary data showing the first application of digital staining to cystoscopy. In Aim 2, we will develop a miniature PS-OCT probe, delivering a technical innovation in size and speed that meets the clinical need for in- office surveillance. Aim 3 will assess the clinical effectiveness of dsWLC+PS-OCT by comparing its sensitivity and specificity to existing clinical standards, WLC and BLC. Individually, both dsWLC and PS-OCT bring significant innovation to the clinical workflow by improving, respectively, the sensitivity and specificity of CIS detection. Used together, they will inspire a new paradigm for the bladder cancer surveillance workflow to increase confidence in detection and eradication of high-grade disease, lower morbidity due to unnecessary biopsies, lower BC recurrence and progression, bring significant healthcare savings and raise quality of life.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary/Abstract Memory CD8+ T cells are seeded throughout lymphoid and non-lymphoid tissues in the aftermath of acute infection. During this process, differentiation occurs into functionally distinct circulating and tissue-resident subsets which can then persist for years, decades, or even life. However, our understanding of this remarkable longevity is largely confined to studying circulating populations in homeostasis, neglecting the preponderance of tissue-resident memory T cells in non-lymphoid tissues and frequent perturbations caused by infection, inflammation, physiological and metabolic changes, etc. Through the proposed studies, the applicant will begin to address this knowledge gap by establishing how preexisting bystander memory CD8+ T cell subsets are maintained during homeostasis and infection via flexible use of cytokines, as addressed with infection models and cytokine therapy. Despite variable requirements for IL-15 between different memory CD8+ T cell populations, the applicant recently published that IL-15 sensitivity is a shared feature across memory subsets that operates within subset- and tissue-specific constraints. Dr. Jarjour proposes that as part of the memory CD8+ T cell program, memory cells gain the capacity to promiscuously utilize many different cytokines, thereby gaining resilience to stark alterations in availability during infection and other perturbations. This flexibility appears to operate within the confines of tissue- and subset- specific regulation, which the applicant will elucidate using his expertise in studying resident immune cells. Beyond revealing a key mechanism supporting durability of memory CD8+ T cells, these studies have implications for immunotherapies to expand memory CD8+ T cell populations, including during vaccination and cancer. The data generated through this proposal will form the basis for an R01 application and will position Dr. Jarjour for an independent career in basic immunology research, with long-term repercussions for human therapies.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Neuropsychiatric disorders, prevalent in nearly half of the U.S. population over a lifetime, are increasingly linked to immune dysregulation. Among these, allergic inflammation has emerged as a key contributor, highlighting an understudied connection between the immune system and mental health. Animal models reveal a causal relationship between allergic inflammation and heightened avoidance behaviors, a core symptom of mood and anxiety disorders. Unlike predominantly studied bacterial or viral immune challenges, allergic inflammation represents a distinct T helper cell type 2 (TH2)-mediated response triggered by nonpathogenic environmental stimuli, which activates emotion-related brain centers, including the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA). These regions are critical for regulating social and anxiety-like behaviors. Converging evidence positions interleukin-4 (IL-4), a key TH2 cytokine elevated during allergic inflammation, as a potential modulator of mPFC circuits and their projections to the BLA, driving avoidance behaviors. This project seeks to determine how IL-4 impacts mPFC dynamics and contributes to heightened avoidance during allergic inflammation. In Aim 1, we will investigate the quantitative relationship between mPFC IL-4 and avoidance behavior during allergic inflammation, identify local IL-4-producing cell types, and determine the impact of heightened mPFC IL-4 on mPFC-BLA responses during avoidance. In Aim 2, we will examine how IL-4 modulates mPFC microcircuit activity and alters mPFC-BLA output and its contributions to allergic inflammation-induced neuroadaptations, defining its role as a non-classical neuromodulator. In Aim 3, we will test the necessity of mPFC IL-4Rα in allergic inflammation-associated mPFC-BLA responses and avoidance behaviors. By integrating advanced molecular, cellular, and circuit-level approaches, this research will uncover novel cytokine-driven mechanisms underlying behaviors associated with neuropsychiatric disorders and identify new immune-based therapeutic targets to address these complex disorders.

NIA - National Institute on Aging

Cytomegalovirus (CMV) is a common beta herpesvirus with over half of adults in the US infected by age 40 and higher seroprevalence among women than men. Though most acute CMV infection in immunocompetent individuals is mild or asymptomatic, following acute infection the virus remains in a latent state with the potential for reactivation across the lifecourse increasing risk of the creation of a chronic inflammatory state, a well appreciated component of accelerated biological aging. Chronic inflammation from any cause can lead to deleterious effects across all organ systems, resulting particularly in later midlife increased risk of metabolic and cardiovascular disease (CVD) in women. There has been mixed evidence implicating CMV seropositivity (CMV+) in the development of CVD and CVD-related mortality. A major limitation of many studies of CMV+ and CVD risk are that such studies do not adequately capture the critical window of physiologic and inflammatory changes that occur in women during the midlife. In the proposed K01, I will obtain the necessary training in aging and field methods to address these research gaps and pursue an independent research career. My research objectives are to a) describe the midlife prevalence of CMV+ within the SWAN cohort and relate CMV+ to subclinical cardiovascular outcomes; b) examine the effect of midlife inflammation on the relationship between CMV+ and carotid intima media thickness; and c) explore changes in IgG antibody level of multiple herpesviruses across the midlife, and to examine the relationship between individual-level change in IgG level and subclinical CVD outcomes. I hypothesize that that individuals with prior CMV infection will have worse subclinical CVD outcomes than those without CMV, particularly in the absence of other common inflammatory conditions such as morbid obesity and type 2 diabetes. To test these hypotheses, I will utilize longitudinal data and banked specimens from the Study of Women’s Health Across the Nation (SWAN), a multi-site cohort of midlife women transitioning into late adulthood. I will conduct this work at the University of Michigan School of Public Health, supported by an interdisciplinary research team that will guide my training in 1) aging and cardiovascular disease epidemiology; 2) immunology and immune-related aging; and 3) practical skills in the development and implementation of prospective data collection methods. By thoroughly evaluating the connections between CMV, midlife inflammation, and CVD we can improve preventative care by identifying those who might be at increased risk for CVD regardless of the presence of other risk factors. This research will also underscore the importance of nontraditional risk factors for cardiovascular disease in women. This grant is critical to meeting the National Institute on Aging’s strategic goal of better understand the biology of aging and its impact on the prevention, progression, and prognosis of disease, and the NIH Initiative on Women’s Health Research goal of developing personalized prevention strategies for cardiovascular disease in women. This award will help launch my independent research career evaluating the etiologic intersections of chronic and infectious disease.

OD - NIH Office of the Director

PROJECT SUMMARY / ABSTRACT Mustard agents, in particular sulfur mustard and nitrogen mustard, can pose potent threats to both Service Members and civilians by penetrating exposed tissues and resulting in devastating effects on myriad organs, among which the ocular surface is the most vulnerable. Around 40% of exposed victims who survive attacks of mustard suffer from ocular problems, with severe corneal sequelae termed mustard gas keratopathy (MGK) that impairs corneal transparency and visual function. The current post-exposure management is very limited and largely ineffective in preventing the development of MGK. We have recently established a mouse model of nitrogen mustard gas ocular damage and show significant loss of corneal nerves as reported in human patients, indicating that impaired neurotrophic support contributes to development of MGK. Among various nerve-derived factors, alpha- melanocyte-stimulating hormone (α-MSH) is critical to ocular homeostasis through exerting anti-inflammatory, cytoprotective, and pro-regenerative function. Our pilot study has demonstrated the effectiveness of α-MSH treatment in preventing the development of persistent corneal epitheliopathy, edema, and opacity, as well as reducing corneal nerve and endothelial loss, in mice exposed to nitrogen mustard. Mechanistically, we demonstrate predominant expression of melanocortin receptor-1 (MC1R), among various α-MSH receptors, in corneal epithelium, suggesting a link of therapeutic effects of topical α-MSH to MC1R signaling pathway. In the current proposal, we thus hypothesize that topical α-MSH treatment mitigates mustard gas corneal damage by primarily activating MC1R-mediated protein kinase A (PKA) pathway at the ocular surface that leads to reduced apoptosis, enhanced regeneration, and suppressed inflammation. The principal objectives of this project are to (i) assess the therapeutic efficacy of α-MSH in preventing the development of MGK; and (ii) determine mechanisms by which α-MSH prevents MGK. To achieve these objectives, two specific aims have been developed: Aim 1: We will test our hypothesis that topical treatment with α-MSH after mustard exposure prevents persistent corneal epitheliopathy and endothelial damage, reduces nerve degeneration, and suppresses corneal inflammation and scarring; and Aim 2: We will test our hypothesis that topically applied α-MSH binds to MC1R in the cornea and activates the PKA pathway to exert its therapeutic function. Successful completion of this project will help validate a potential molecule capable of mitigating mustard- induced ocular damage, and thus lay a foundation for our next steps, involving translational studies to further investigate the function of α-MSH in mitigating sulfur mustard-induced ocular damage.

NIGMS - National Institute of General Medical Sciences

Cells perceive mechanical cues in their local environments, which must be converted into intracellular biochemical signals to modulate cellular physiology and control gene expression. This process of mechanical signal transduction (“mechanotransduction”) is critical for development and frequently dysfunctions in disease states such as cancer. Despite increasing appreciation of its importance for human physiology, the molecular mechanisms of mechanotransduction remain poorly understood, hampering efforts to define mechanistically distinct mechanical signaling pathways, delineate their specific biological functions, and target them therapeutically. The actin cytoskeleton, a network of dynamic actin filaments (F-actin), myosin motor proteins, and hundreds of associated factors, enables cells to mechanically interface with their surroundings. While the cytoskeleton is classically understood as a force generation and transmission apparatus that indirectly facilitates mechanotransduction, our research has provided evidence that actin filaments can also serve as direct molecular force transducers. By developing innovative cryo-electron microscopy (cryo-EM) sample preparation and machine-learning based computational analysis approaches, we have uncovered multiple classes of force- dependent structural transitions in F-actin (elicited by fluid flow and myosin molecular motor forces) that can be discriminated by force-sensitive actin-binding proteins. This work has provided a first direct glimpse at how forces alter protein structure to regulate function. Using biophysical reconstitution and cell biology studies, we have also shown how force-activated F-actin binding by proteins from the LIM (LIN-11, Isl-1 & Mec-3) domain superfamily can coordinate downstream mechanotransduction processes, including repair of physical damage to actin- myosin cables mediated by zyxin and extracellular matrix stiffness-dependent nuclear localization of Four-and- a-Half LIM domains (FHL) transcriptional control proteins. Additionally, we have developed cryo-EM and cryo- electron tomography (cryo-ET) approaches for visualizing crosslinking proteins bridging actin filaments, setting the stage for studying how forces alter the geometry and composition of higher-order cytoskeletal networks in atomistic detail. To build upon this progress, we will now study the structural mechanisms and cellular functions of a ubiquitous class of force-stabilized protein-protein interactions known as catch bonds, which are prominent in cytoskeletal crosslinkers and cell adhesion proteins implicated in mechanotransduction. We will also probe the structural basis of force-activated cytoskeletal engagement by LIM proteins, focusing on both individual actin filaments and cytoskeletal networks in vitro and in cells, as well as scrutinize the nuclear localization and gene regulatory mechanisms of FHL proteins. In the near term, our efforts will provide detailed mechanistic insights into mechanical signaling pathways, facilitating precise dissection of their functions in vivo. In the longer term, our work may guide the development of chemical probes and therapeutics which selectively target mechanotransduction.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY This proposal for a K01 Mentored Career Development Award details a Career Development Training Plan and Research Strategy to facilitate the candidate’s transition to an independent investigator role in diabetes research. In particular, the candidate’s long-term research goal is to make impactful discoveries that will enable a cell-based therapy to become a viable and widely-used treatment option for type 1 diabetes (T1D), alleviating the hardships and complications associated with this disease. To guide the candidate’s transition to independence, the Career Development Training Plan integrates a scientific research proposal investigating new aspects of β cell development and maturation, a mentoring team of experts in stem cell and β cell biology, and the world-class research environment at Washington University in St. Louis. T1D results from the selective autoimmune destruction of the insulin-producing β cells in pancreatic islets. Studies have shown that transplanting human cadaveric pancreatic islets into T1D patients reduces or eliminates the need for exogenous insulin injections, indicating that replacing the destroyed β cells can serve as a functional cure for insulin-dependent diabetes. However, issues with human donor islet supply, quality, and immunogenicity have limited the widespread use of this approach. In an effort to generate an unlimited supply of highly functional islets for cell therapy, excellent progress has been made in the generation of stem cell-derived islets (SC-islets) via direct differentiation protocols. In particular, these cells are able to replicate the first and second phase insulin secretion kinetics of primary β cells, the ability to cure severely diabetic mice within two weeks of transplantation, and further maturation after long-term transplantation. Despite these remarkable advancements, current generation SC-islets still lag behind primary human islets in terms of insulin secretion and overall islet composition. Emerging evidence has demonstrated that microenvironmental cues (e.g., substrate composition and mechanical properties) sensed by cells through their actin cytoskeleton play important signaling roles in cell behavior and fate selection in several model systems, but actin’s role in the directed differentiation of hPSCs to endodermal cell types has been very limited. To further enhance the specification to and maturation of SC- islets using these principles, this proposal seeks to leverage microenvironmental cues transduced through the actin cytoskeleton and its downstream pathways to improve pancreatic specification during gut tube organogenesis as well as during endocrine cell maturation. These studies aim to improve specification to pancreatic β cells, eliminate other undesired cell types (e.g., enterochromaffin cells), as well as enhance the functional maturation and identity of these β cells. Successful completion of these objectives will not only improve the clinical effectiveness of SC-islets but will also uncover fundamental insights into the biology of how cytoskeletal state influences endodermal cell development.