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Fremont Floating Wetlands

The project will install artistic educational signage that will bring attention and promote understanding of the floating wetlands that are adjacent to the protection piers at the Fremont Bridge along the Burke Gilman trail. These floating wetlands on the north side of the Lake Washington Ship Canal provide opportunities for educational information and engagement to promote innovative ways of bringing salmon habitat back to the urban water edges. The anticipated project completion date is February 28, 2022.

Discover Arts in the Park

Discover Arts in the Park in will organize an outdoor event to explore climate change through the lens of art. Symphony for Climate Change will take place on August 17, 2019 at the upper field of the Daybreak Star Center in Discovery Park. The event will feature a multimedia symphony, dance performances, and science presentations that will initiate discourse and motivate people to see what practical steps they can take in their own lives and communities to combat climate change.

OD - NIH Office of the Director

Abstract Improvement of experimental rigor and reproducibility is critical to enhance biomedical research. Zebrafish (Danio rerio) are widely used organisms in numerous biomedical research fields, including developmental biology, genetics, neurobiology, /toxicology, and more. Zebrafish also are a key component of New Approach Methodologies (NAMs), as they provide the only in-tact vertebrate system within this category. While many aspects of zebrafish environmental factors have been standardized across laboratories, there remain many elements that have not been systematically studied to account for how they affect variability of measured biological endpoints such as behavior, organ growth, morphology, nutrient content, and xenobiotic responses. To address this data gap and enhance shared resources across our community, we propose to acquire new, state of the art equipment capable of recording, measuring, and analyzing multiple parameters simultaneously: 1) embryo incubators that monitor and control light, temperature, and humidity, 2) a multi-camera array microscope for morphology and behavior endpoints, and 3) an aquatics data system to monitor, record, and automatically adjust water quality parameters. Leveraging four independently managed zebrafish facilities at the University of Massachusetts Amherst, we aim to systematically evaluate extrinsic factors affecting biological endpoints across multiple physiological and organ systems in zebrafish at embryonic/larval (rearing media, light cycle, vessel size, population density, and feeding) and parental life stages (diet), and monitor other environmental measures (e.g. fish facility water quality parameters, temperature). Outcomes affecting developmental toxicology impacts on embryonic development, pancreas and liver structure and function, antioxidant responses, behavior, neurogenesis, craniofacial development and skeletal mineralization, will incorporate extrinsic factors to determine if they are modifiable variables. This study will lead to identification of new mechanistic bioindicators and biomarkers that can be utilized by others to improve reproducibility, rigor, and translation of findings from zebrafish to human health outcomes.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Globally, approximately 282 million incidences and 610,000 fatalities were attributed to malaria in 2024 (World Malaria Report, 2025). The recent increase in cases highlights the urgent need for a more comprehensive understanding of the etiological agent of the disease. The protozoan parasite responsible for causing malaria, Plasmodium falciparum, remains the most prevalent and lethal species among the Plasmodium genera. Malaria persistence can be partly attributed to the growing resistance of the Plasmodium parasite to currently available antimalarial drugs (World Malaria Report, 2025). An additional factor to the difficulty of eradication efforts is the highly competitive nature of Plasmodium falciparum populations in Africa, where the emergence and spread of drug resistance pose significant challenges to malaria control1–4. I propose conducting bulk segregant analyses (BSAs), both with and without artemisinin (ART) pressure, with sample collection at multiple time points. Previous BSAs under drug pressure have successfully uncovered key mutations such as pfCRT for chloroquine (CQ) resistance and pfK13 for ART resistance5,6. However, these methodologies required careful refinement and are still being optimized for other drugs, such as piperaquine (PPQ). Based on my preliminary data and prior in vivo pooled assays, I hypothesize that competitive dynamics and resistance mechanisms interact in ways that complicate resistance detection and parasite population structure under temporary selective pressure7–9. Combining genetically diverse parasites in pooled assays can confound the detection of resistance when drug sensitivity varies among the population. In such cases, the resistant parasite can only be detected through genetic sequencing and tracking the most abundant parasite. Furthermore, competition among parasites plays a significant role in population dynamics. More fit parasites, even if drug-sensitive, may outcompete resistant parasites and dominate the population after treatment. Interestingly, moderately resistant and moderately fit parasites may emerge as dominant when no parasites exhibit both high fitness and high resistance. Utilizing the experimental structure of a competitive growth assay in a genetic cross will assess fitness-resistance trade-offs by monitoring allelic shifts under both treated and untreated conditions. These experiments will provide insights into how genetic architecture influences competitive outcomes and facilitates the spread of resistant parasites. This work aligns with global malaria control efforts by providing critical data on the evolutionary dynamics of resistance, informing surveillance strategies, and guiding intervention policies.

NIBIB - National Institute of Biomedical Imaging and Bioengineering

Project Summary/Abstract Deep learning (DL)-based image denoisers have gained significant attention in positron emission tomography (PET) due to their ability to enhance image quality in low-count or short-duration scans. These models hold substantial promise for reducing radiation dose, minimizing scan time, and improving diagnostic performance – particularly for vulnerable populations and in resource-limited settings. However, DL-based denoisers may introduce artifactual features, including false-positive or false-negative lesions, that are not supported by the underlying data. These artifacts remain poorly understood and pose a critical barrier to the safe clinical adoption of AI-enhanced image reconstruction. This project aims to systematically evaluate, quantify, and model the risk of artifacts in DL-denoised PET images. Using a Monte Carlo-based lesion embedding framework developed by our team (DIANA), we will simulate artificial hepatic lesions in real human PET data to establish in-vivo ground truth. Low-count images of various noise levels will be generated through random downsampling of high-quality PET data acquired on the EXPLORER total-body PET/CT scanner. These images will subsequently be denoised using a state-of-the-art 3D diffusion probabilistic model, and artifacts will be detected using a novel combination of gradient-domain image differencing and generalized scan statistics. Furthermore, we will systematically investigate how imaging and anatomical factors that are available at scan time influence the probability of wrongfully added lesions in DL-denoised PET images. To that end we will develop a logistic regression model to quantify the conditions under which artifacts are most likely to occur, thus, providing a prototype predictive framework for risk stratification and clinical decision support. Input features will include image noise level as well as anatomical and patient-specific variables (e.g., BMI, and amount of injected radioactivity). This work enables a scientific assessment of the safety and fidelity of AI-based denoising methods, ensuring they support rather than compromise clinical decision-making and the broader goals of translational science.

National Institutes of Health

<p>Through this Notice of Funding Opportunity (NOFO), the National Cancer Institute (NCI) intends to support research projects that employ state-of-the-art cancer biology approaches and preclinical model systems to investigate the biological effects of radiation emitted by radionuclides used in radiopharmaceutical therapy (RPT). The focus of this initiative is to advance mechanistic understanding of how different forms of radionuclide-emitted radiation affect normal tissues, tumor cells, and the tumor microenvironment, and how these effects can be leveraged to improve therapeutic outcomes. This NOFO will support the&nbsp;<strong>Systematic Testing of Radionuclides in Preclinical Experiments (STRIPE)</strong>&nbsp;program. The overarching goal of STRIPE is to stimulate multidisciplinary research that integrates cancer biology, radiation biology, radiochemistry, imaging, dosimetry, and preclinical modeling. Funded projects are expected to generate fundamental biological insights that can serve as the foundation for the development of new targeting strategies, optimized treatment regimens, and innovative combination approaches for RPT, ultimately leading to more effective and precise anticancer therapies.</p><p>This NOFO consolidates prior exploratory/developmental and research project funding mechanisms to streamline the application process and sustain momentum in this critical research area. The applicants have the option of submitting either for exploratory/developmental research projects with a project period of up to 2 years or for research projects with a project period of 4 to 5 years. Collectively, the STRIPE program is intended to broaden the scientific base of RPT research, lower barriers to entry for cancer biology investigators, and accelerate the generation of reproducible, mechanistically informed data that will enable more effective and personalized use of radiopharmaceutical therapies in cancer care.</p>

National Institutes of Health

Through this Notice of Funding Opportunity (NOFO), the National Cancer Institute (NCI) intends to support research projects that employ state-of-the-art cancer biology approaches and preclinical model systems to investigate the biological effects of radiation emitted by radionuclides used in radiopharmaceutical therapy (RPT). The focus of this initiative is to advance mechanistic understanding of how different forms of radionuclide-emitted radiation affect normal tissues, tumor cells, and the tumor microenvironment, and how these effects can be leveraged to improve therapeutic outcomes. This NOFO will support the Systematic Testing of Radionuclides in Preclinical Experiments (STRIPE) program. The overarching goal of STRIPE is to stimulate multidisciplinary research that integrates cancer biology, radiation biology, radiochemistry, imaging, dosimetry, and preclinical modeling. Funded projects are expected to generate fundamental biological insights that can serve as the foundation for the development of new targeting strategies, optimized treatment regimens, and innovative combination approaches for RPT, ultimately leading to more effective and precise anticancer therapies.This NOFO consolidates prior exploratory/developmental and research project funding mechanisms to streamline the application process and sustain momentum in this critical research area. The applicants have the option of submitting either for exploratory/developmental research projects with a project period of up to 2 years or for research projects with a project period of 4 to 5 years. Collectively, the STRIPE program is intended to broaden the scientific base of RPT research, lower barriers to entry for cancer biology investigators, and accelerate the generation of reproducible, mechanistically informed data that will enable more effective and personalized use of radiopharmaceutical therapies in cancer care.

NHLBI - National Heart Lung and Blood Institute

ABSTRACT Cardiovascular disease (CVD) is the number one cause of death for women in the U.S.. Endometriosis is a common, female-specific condition defined by endometrial-like tissue thriving outside the uterus that affects ~200 million women globally. Several studies show that endometriosis is associated with higher CVD risk and other cardiometabolic conditions, however, endometriosis patients do not present with traditional CVD risk profiles. Indeed, our prospective study confirmed that endometriosis is associated with CVD risk independent of traditional CVD risk factors. Therefore, there is an urgent need to elucidate the underlying pathophysiology and biological pathways linking endometriosis with subsequent CVD risk, which will discover unique, potentially preventable and treatable, CVD mechanisms specific to women. Our long-term goal is to accelerate novel strategies to reduce CVD incidence in women through a life-course approach. We will identify systemic metabolic alterations in endometriosis patients and their associations with future CVD risk. Our central hypothesis is that systemic metabolic dysregulation occurs in women with endometriosis starting in adolescence, leading to increased CVD risk in mid-life. Our preliminary evidence shows that adolescents with endometriosis have higher blood levels of ceramides and phosphatidylcholines compared to those without, which are known to contribute to CVD pathophysiology. Our data also suggest that these metabolites are persistently elevated despite surgical removal of endometriotic lesions. The rationale for this project is that understanding systemic metabolic alteration in adolescents and young adults with endometriosis will elucidate the biologic underpinning of endometriosis as a female-specific risk factor for CVD as well as discover novel markers that will allow detection of early metabolic dysregulation leading to future CVD risk. We will apply state-of-the-art metabolomics technology and leverage the deeply phenotyped data and biospecimens from six existing prospective cohort studies: The Women’s Health Study: From Adolescence to Adulthood (A2A; n=1,002), the Nurses’ Health Studies [NHS (n=7,735), NHSII (n=3,410)], the Women’s Health Initiative (WHI; n=2,306), UK BioBank (UKBB; n=~145,000), MGB Biobank (MGBB; n=~30,000). In Aim 1, we will determine the endometriosis-related metabolic dysregulation profile in adolescents (A2A). In Aim 2, we will Identify the endometriosis-related metabolic dysregulation profile in adults (NHSII). In Aim 3, we will develop and validate the metabolite-based endometriosis score and examine its association with subsequent CVD risk using data from six cohorts. Results from this study will 1) identify systemic metabolic alterations linking endometriosis and CVD and 2) identify novel CVD risk biomarkers that can be assessed as early as adolescence to young adulthood. Determining the systemic metabolic alterations in women with endometriosis that emerge and persist from adolescence to adulthood and their association with future CVD risk will lead to novel targeted strategies to detect early indications of a change toward declined cardiometabolic health and formulate preventive interventions in women.

NIGMS - National Institute of General Medical Sciences

Summary The goal of our research is to discover the central principles that govern cellular adaptation. We aim to understand how cells achieve adaptive gene-expression states, both during short-term physiological adaptation and long-term adaptive evolution. We investigate these phenomena on a systems-level, often necessitating observations, perturbations, or analyses that are beyond the scale and precision of existing methods. Thus, our laboratory also develops new enabling technologies and computational methods. In this R35 application, we seek support for three NIGMS-related projects: (1) Cellular adaptation by stochastic tuning of gene expression. We have discovered a powerful new mechanism, that we call stochastic tuning, by which eukaryotic cells adapt to extreme or novel challenges. During stochastic tuning, cells utilize transcriptional noise to randomly change the expression of individual genes, and to actively reinforce those changes that improve the overall health of the cell. Stochastic tuning therefore enables cells to prospectively explore novel gene expression states that enable adaption to challenges in real time—including conditions never previously encountered—thereby bypassing the need for pre-determined hardwired regulatory programs. We have compelling new evidence that stochastic tuning is the key underlying mechanism for non-mutational cancer chemotherapy resistance, recognized as a major barrier to effective cancer therapies. We are utilizing CRISPR-interference and largescale reporter assays to define the critical protein and DNA effectors of stochastic tuning in yeast and to mechanistically determine their roles using chemical/genetic/optogenetic perturbations of single cells in well-controlled microfluidic experiments. (2) Genetic basis of microbial habitat adaptations. We have developed a versatile computational framework to conduct genotype-habitat association at the tree-of-life scale, enabling discovery of genes that underlie microbial colonization of specific habitats. By applying this analysis to the gut microbiome, we have discovered many highly conserved factors that strongly contribute to gut colonization. We are using functional genomics technologies to efficiently determine the molecular mechanisms by which these factors enable gut colonization. In addition, we are developing state-of-the-art deep learning and protein language models to improve the sensitivity/specificity of genotype-habitat association, enabling large-scale microbial engineering for diverse biomedical applications. (3) Global mapping of all-against-all molecular interactions in a single tube. We have recently developed a powerful technology for coupling in vivo expressed proteins to their encoding messenger RNAs, enabling a diverse array of proteomic assays to be performed by using DNA- sequencing as a readout. We propose to develop this platform to enable routine comprehensive all-against-all protein-protein and protein-DNA interaction studies on the timescale of days. This technology promises to transform our ability to rapidly map molecular network interactions under dynamic physiological conditions, an essential capability in the era of AI-enabled biology.

NHLBI - National Heart Lung and Blood Institute

Tachycardia, or abnormally fast heart rate, is an important risk factor for cardiovascular morbidity and mortality. Prolonged tachycardia is known to induce cardiomyopathy in patients who have no prior structural heart diseases. Moreover, transient tachycardia, frequently observed in heart failure patients, can exacerbate the cardiovascular outcome. However, very little is known about the molecular drivers underlying tachycardia-induced cardiac dysfunction. This gap in our knowledge hinders the development of more effective heart failure treatment, especially for patients with hard-to-control tachycardia. This K99/R00 proposal will leverage recent advances in induced pluripotent stem cell (iPSC), tissue engineering, and multiomics technologies to uncover the molecular signaling pathways critically involved in the pathology of tachycardia-related heart disease. The applicant, Dr. Chengyi Tu, has established and validated an in vitro tachycardia platform using engineered heart tissue (EHT). In Aim 1, Dr. Tu will perform metabolomic and transcriptomic profiling of EHTs with or without tachypacing. To validate the physiological relevance of the EHT model, canine samples from tachypacing-induced heart failure will also be profiled. Preliminary data from the EHTs and the canine samples coherently indicate that the disruption of glycolysis homeostasis may underly the impairment of cardiac function by tachycardia. Metabolomics analysis shows that tachypacing in EHTs resulted in a selective accumulation of glycolysis intermediates such as glyceraldehyde 3-phosphate (GA3P) and 3-phosphoglycerate (3PG). Interestingly, promotion of fatty acid metabolism accelerated the recovery of cardiac contractility in tachypaced EHTs. Based on these novel results, Aim 2 will focus on elucidating how different glycolysis intermediate metabolites affect the function of cardiomyocytes, which has yet to be systematically examined. Lastly, Aim 3 (R00 phase) will employ state-of-the-art mass spectrometry workflow to screen for novel binding targets of glycolysis intermediates in cardiac cells, and examine the potential therapeutic benefits of manipulating these targets. This K99/R00 proposal will be guided by an excellent mentoring team with diverse expertise, including mentor Dr. Joseph Wu (iPSCs and cardiac biology), co-mentor Dr. Sanjiv Narayan (arrhythmia), advisors Dr. Michael Snyder (genetics and multi-omics), Dr. Yuqin Dai (metabolomics), Dr. Stanley Qi (CRISPR interference) and Dr. Beth Pruitt (bioengineering), as well as collaborators Dr. Fabio Recchia (canine model) and Dr. Donald Bers (cardiac physiology). To sum up, the completion of the proposed study will significantly advance our mechanistic understanding of how tachycardia adversely affects the heart, thereby creating new opportunities for therapeutic interventions. The proposed training will significantly strengthen and expand Dr. Tu’s research expertise, providing substantial momentum to his transition toward an independent cardiovascular researcher.

Dept of the Army -- Materiel Command

**UPDATE 5 APRIL 2024: The proposal submission date has been updated to 24 April 2024. The FOA has been amended to reflect this submission date and include a Question and Answer document based on questions received from interested applicants. Other than the updated proposal submission date in the FOA, the actual FOA Amendment has not been changed. However, the answers provided in the Q&amp;A document are considered part of the FOA Amendment.** **CYCLE 2 UPDATE 20 MARCH 2024 - THE OPPORTUNITY WEBINAR FOR CYCLE 2 WILL BE HELD ONLINE VIA MS TEAMS AT 1500 EDT ON 22 MARCH 2024 AT THE FOLLOWING LINK: https://dod.teams.microsoft.us/l/meetup-join/19%3adod%3ameeting_5fa41fe6fa874484b473d8a6ba7921c6%40thread.v2/0?context=%7b%22Tid%22%3a%22fae6d70f-954b-4811-92b6-0530d6f84c43%22%2c%22Oid%22%3a%22e9f6fc39-8f22-44e5-8bd0-64f0cde32305%22%2c%22IsBroadcastMeeting%22%3atrue%7d **UPDATE 14 MARCH 2024 - CYCLE 2 HAS BEEN POSTED TO THE ANNOUNCEMENT. PLEASE REVIEW THE UPDATED ANNOUNCEMENT IN FULL FOR SUBMISSION TIME, UPDATED TOPIC, AND FUNDING AMOUNT AND SCHEDULE CHANGES FROM CYCLE 1** TACTICAL BEHAVIORS FOR AUTONOMOUS MANEUVER COLLABORATIVE RESEARCH PROGRAM (TBAM-CRP) Future Army forces will be called upon to operate and maneuver in multi-domain operations (MDO), against a modern and capable peer adversary. The battlefield of the future may impose additional constraints on maneuver forces such as disruption in communication as well as positioning services. To field a highly capable fighting force in this future battlefield, novel tactics and doctrines leveraging nascent technologies in robotics and autonomous systems (RAS) will need to be developed. Teams of RAS will serve an increasingly critical role in the future force to deliver situational awareness, defend key locations or positions, or take point in dynamic and hazardous situations. Resilience to disruptions, failures, or unexpected scenarios, is a key quality for teams of RAS to operate alongside other future Army forces. The US Army Combat Capabilities Development Command (DEVCOM) Army Research Laboratory (ARL) is focused on developing fundamental understanding and informing the art-of-the-possible for warfighter concepts through research to greatly improve the scope of mission capabilities of teams of RAS, develop robust and resilient approaches to plan under extreme conditions of uncertainty, to learn coordinated strategies for groups of agents to achieve a common objective, all within a complex maneuver environment including adversaries. The Tactical Behaviors for Autonomous Maneuver Collaborative Research Program (TBAM-CRP) is focused on developing and experimentally evaluating coordinated and individual behaviors for small groups of autonomous agents to learn doctrinal as well as novel tactics for maneuvering in military relevant environments. The TBAM-CRP will leverage developments in other internal and extramural programs as well as identify new research directions to find novel solutions to these maneuver problems in analogical simulations representing complex realistic terrain. The Tactical Behaviors for Autonomous Maneuver Collaborative Research Program (TBAM-CRP) will consist of a series of sprint efforts executed with annual program reviews. Each topic will be focused on addressing a different set of scientific areas which will support the research aims of an associated ARL researcher from a related internal essential research program (ERP) or mission-funded program. The TBAM-CRP has been developed in coordination with other related ARL-funded collaborative efforts (see descriptions of ARL collaborative alliances at https://www.arl.army.mil/business/collaborativealliances/) and shares a common vision of highly collaborative academia-industry-government partnerships; however, it will be executed with a program model adapted from the Scalable, Adaptive, and Resilient Autonomy (SARA), which established a new paradigm for collaborative research. Some key properties of this new approach are described below: TBAM-CRP sprint topics will be offered on a two-year cycle. Proposals will be solicited for a possible two-year period structured as a first-year pilot followed by a second-year option where the option may be awarded based upon progress assessed at an annual review. The FOA will be amended annually to identify a specific problem statement and scope for that specific cycle. The topics for each cycle will be chosen to address the long-term program goal. Five new topics (Cycles 1-5) are expected in FY22, 24, 26, 28, 30. Each topic will be carefully chosen based on the previous accomplishments in the prior cycle(s), the development of new technologies and capabilities in the broader research and development communities, and the Army s evolving needs for future capabilities. For each topic, funding will be provided to those Recipients selected under a cooperative agreement (CA). Enhanced Research Program funding from ARL or Other Government Agencies (OGAs) may become available during a cycle which provides a mechanism for growth and enhancement within the TBAM-CRP. A proposal should not include any discussion of the Enhanced Research Program. Recipients receiving a CA will be notified and provided details if the opportunity for Enhanced Research Program funding becomes available during their award period of performance. There is no limitation on the place of performance, although on-site collaboration at ARL facilities and with ARL researchers as well as with other Recipients are encouraged. Research outcomes in this program must, at the very least, be demonstrated in sophisticated simulations of relevant environments. Together with ARL collaborators, these results may be adapted for higher TRL experimentation on surrogate platforms at ARL test facilities such as the Robotics Research Collaboration Campus (R2C2) at Graces Quarters, Aberdeen Proving Ground, Maryland. Recipients will be furnished with access to the ARL Autonomy Stack software suite as well as all relevant simulation tools and multi-agent learning support. Recipients will be provided with information about the current state of the Autonomous Systems Enterprise (ASE) with an overview of developments in the associated collaborative research alliances including Distributed and Collaborative Intelligent Systems and Technology (DCIST), Scalable, Adaptive, and Resilient Autonomy (SARA), as well as internal ARL essential research programs including the AI for Maneuver and Mobility (AIMM), Emerging Overmatch Technologies (EOT), and Versatile Tactical Power and Propulsion (VICTOR). Capabilities demonstrated in simulation should reflect significant appropriate developments. This midpoint review is expected to take place as a mini symposium where Recipients can share results with one another along with the ARL community to foster further collaboration. At the end of the second year, a capstone demonstration will be executed by those Recipients receiving an option to their award in a set of simulated relevant environments, either those environment scenarios provided by the Government and other program performers, or optionally of a specific environment developed by the Recipient to exhibit their developed capability. Any system level capability demonstration that can be made with the internal ARL collaborator or description of capability development and program contribution can also be made at this time. These system demonstrations are expected to coincide to foster further integration and adoption with related internal research programs as well as partner organizations from within the DEVCOM, other Army and DoD service branches and agencies, in addition to other government agencies. Proposals that follow the requirements of the FOA will be evaluated in accordance with merit-based, competitive procedures. These procedures will include evaluation factors and an adjectival and color rating system. A review team, consisting of a qualified group of Government scientists and managers will evaluate the compliant proposals and provide the results of that evaluation to the decision-maker for the Government. Relevant internal research program materials approved for public release and contact information will be provided to potential proposers during introductory presentations to help facilitate identification of collaboration between proposers and individual ARL researchers or internal research programs. Additional connections to ARL programs can be identified during the proposal review process. Eligible applicants under this FOA include institutions of higher education, nonprofit organizations, and for-profit organizations (i.e., large and small businesses) for scientific research in the knowledge domains outlined throughout this Funding Opportunity. Federally Funded Research and Development Centers (FFRDC) may propose as well, with effort as allowed by their sponsoring agency and in accordance with their sponsoring agency policy.

Soul Societies

Soul Societies will provide art instruction and cultural exploration to 50 youth in Seattle free of charge. Youth will take twenty two-hour classes approximately weekly from September 2017 to January 2018 at Gravity Plus0 (1000 South Weller Street). The focus will be on cultural folklore and development of a book featuring the youth's work, copies of which will be given free to neighborhood and community groups. Youth aged 6-12 will be recruited from the International District and neighboring areas. There will also be a signup table at the Banh Mi Fest in the ID on August 27, 2017. Instructors will be a variety of professional designers/community artists. Youth will showcase artwork at the Tet in Seattle event on Saturday, February 17, 2018, at Seattle Center's Fisher Pavilion and at a Soul Societies celebration in June 2018. These classes will provide a creative space for the youth to share and learn about their cultural history through artistic and literary expression.

NIAID - National Institute of Allergy and Infectious Diseases

Abstract Chimeric Antigen Receptor (CAR) T-cells have emerged as a powerful immunotherapy for various forms of cancer and show promise in treating HIV-1 infection. Our studies in humanized mice and non-human primates (NHPs) have demonstrated that hematopoietic stem cells (HSPCs) based CAR therapy could provide life-long engraftment and production of functional CAR-T, CAR-NK and CAR-Macrophages (CAR-M), resulting in significantly reduced viral rebound after ART withdrawal. These studies underscore both the feasibility and efficacy of HSPCs-based CAR therapy. However, major challenges remain to achieve sustained viral remission in the absence of ART with current engineered immunity approaches. Mounting evidence has shown that environmental factors, such as metabolic regulation, innate signaling and chronic inflammation greatly impact in vivo function and persistence of engineered immune cells. Here we propose to investigate pharmacological interventions to enhance metabolism of engineered cells, improve effector functions, reduce immune suppression, prevent/restore immune exhaustion, and enhance memory formation of engineered CAR cells in vivo. Building on our extensive work on CAR engineered immunity, innate signaling and immune metabolism, we will 1) improve CAR-MQ, CAR-T and CAR-NK effector function and enhance expansion of CAR T cells by modulate immune metabolism with lactase targeting enzymes; 2) promote CAR-T cell persistence, memory formation and prevent exhaustion by targeting mTOR (mammalian target of rapamycin) pathway; and 3) Optimizing CAR-cell function by temporal integration of metabolic and immunoregulatory modulators. To minimize off-target effects and toxicity, we will leverage our established nonocapsule platform to deliver these pharmacological modulators specifically to CAR-expressing cells. We hypothesize that targeted immune modulation will maximize the in vivo function and persistence of multilineage CAR cells, providing a robust strategy towards a functional HIV cure.

NEI - National Eye Institute

Project Summary/Abstract Photoreceptor degeneration in diseases such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP) causes irreversible blindness, affecting millions worldwide with no current treatment capable of restoring naturalistic vision. In the Chichilnisky Lab at Stanford University, our goal is to develop the first treatment capable of restoring naturalistic vision using an electronic retinal implant. This device will operate by stimulating the surviving output cells of the retina, retinal ganglion cells (RGCs), at single-cell resolution to replicate the intricate signals the healthy retina would have sent to the brain. Achieving this goal requires a detailed understanding of various RGC types, their physiological properties, and their responses to electrical stimulation in the degenerating retina. To build this understanding, I will develop computational approaches for cell type identification and conduct ex vivo electrophysiology experiments using large-scale multielectrode arrays to track and electrically stimulate RGCs in degenerating retinas. In the proposed research, I will study RGCs in the retina of a rat model of retinal degeneration (Royal College of Surgeons) due to its practicality and our experience with rat retinas. I will first catalog RGC types in healthy rat retinas using their distinct responses to light, then develop computational approaches to identify RGC types based solely on their electrical features. This capability is crucial for application in blind retinas, where light responses are absent. Next, I will apply this approach to track and characterize RGC types at different stages of degeneration in a rat model of RP, allowing me to observe how degeneration affects RGC physiology and electrical targetability. Finally, I aim to control the activity of individual RGC types via electrical stimulation to evaluate the feasibility of restoring visual signals in degenerated retinas with cell type-specific precision. This research will make possible the identification and control of distinct cell types in the degenerating retina for the first time. This will be a crucial component of a future cell type-specific retinal implant for vision restoration and will advance our understanding of functional cellular changes during neurodegeneration. This research will be conducted using state-of-the-art multielectrode arrays under the mentorship of Prof. Chichilnisky, a world leader in retinal neurophysiology. I will receive training in ex vivo electrophysiology, neuroscience, machine learning, and scientific communication within an academic environment that fosters interdisciplinary collaboration and is home to experts in engineering, computation, and vision science. Access to coursework, workshops, and seminars will further support all aspects of the proposed work. This training will directly advance my long-term goal of developing a bi-directional epiretinal implant to restore naturalistic artificial vision and deepen our understanding of visual neuroscience.

NIH

Background. High grade serous epithelial ovarian cancer (EOC) is the deadliest gynecologic cancer and has one of the highest rates of venous thromboembolic (VTE) complications. As the number of female Veterans is rapidly growing, the incidence of EOC has also significantly risen. An estimated 5–25% of ovarian cancer patients will have a VTE within the first two years of cancer diagnosis and these women will have lower survival rates than their counterparts without VTEs. The prothrombotic potential of EOC has been directly linked to overexpression of specific coagulation factors, among them Factor XII (FXII), and proinflammatory chemokines that contribute to exuberant thrombin activity in the circulation and the tumor niche. Our preliminary studies in human ovarian tumor samples show that FXII is expressed by cancer cells themselves and tumor-associated myeloid cells. In a very aggressive mouse model of EOC, FXII deficiency conferred protection from deep vein thrombosis in a model of inferior vena cava ligation. FXII deficiency also dramatically halted tumor peritoneal dissemination and metastatic burden. We identified that neutrophils endow EOC cancer cells with proinvasive properties, which are reversed by genetic deletion of FXII. These findings support the central hypothesis that targeting FXII functions has the potential to improve prothrombotic risk and perturb tumor-host interactions to suppress tumorigenesis and metastasis. To test our hypothesis, we propose to: 1) characterize the selective contribution of canonical and non-canonical FXII functions on systemic hypercoagulability in ovarian cancer; 2) determine the mechanisms linking FXII-uPAR to tumor growth and progression; 3) examine if targeted inhibition of FXII functions will limit EOC progression and suppress EOC-associated thrombophilia. Innovation. Our proposed research to characterize the bi-directional relationship between thromboinflammatory pathways and tumor biology represents a new strategy to solve the problem of EOC progression and cancer- associated thrombosis, the two leading causes of death among ovarian cancer patients. Since FXII is one of the few proteins that affects thrombosis without impacting hemostasis, the proposed work will further define a target whose inhibition is not accompanied by an increased bleeding risk. In this project, we use a state-of-the-art luminescent mouse mode for in vivo analysis of intraperitoneal tumor burden, patient-derived xenograft (PDX) models, novel modified peptides and cutting-edge nanomedicine to interfere with FXII functions in vivo. Significance and Impact to Veterans Healthcare. Women Veterans are the fastest growing segment of new VA users. As a result, BLR&D announced “Women Veterans’ Health” in its list of priority research areas. A recently conducted VA study found an increased incidence of ovarian cancer in active-duty Veteran females less than 45 years of age compared to the general US population. The potential immediate impact of our research is the establishment of novel scientific insight regarding the crosstalk of thrombo-inflammatory processes in ovarian cancer pathology. Most importantly, the envisioned long-term impact of our research will be realized via the clinical translation of our novel findings, given the current statistics indicating that 2,600 members of the military have spent over 14,000 days in hospitals for treatment of ovarian cancer in the last five years. Path to translation/implementation. We have secured non-provisional patents for all major components of this project i.e., composition of matter and use in disease for: i) peptide sequences to target the FXII-uPAR interaction; ii) neutrophil elastase-binding peptides, iii) neutrophil-targeted nanoparticles. A considerable advantage of this application is that all peptide sequences are human-derived and soluble in aqueous solution, the nanoparticle formulations utilize the same liposomal composition as other licensed drugs (e.g., liposomal doxorubicin, amphotericin B). We envision that completion of studies proposed in this application will support a pharmacology package required for pre-IND discussions with the FDA, as well as for customer discovery and acquisition source feedback from potential licensors.

NCI - National Cancer Institute

PROJECT SUMMARY Metabolic reprogramming is a hallmark of cancer and potential opportunity for therapeutic intervention. The study of cancer metabolism, to its detriment, has largely focused on central carbon metabolism, such as glycolysis, the pentose phosphate pathway, and the citric acid cycle. Accordingly, less attention has been given to investigating the functional roles of nitrogen metabolism, especially how carbon and nitrogen metabolism are interconnected, and its impact on tumorigenesis. Glycosylation presents an excellent model to broaden the field by studying how the interplay of carbon (glucose) and nitrogen metabolism (amino acids and nucleotides) contributes to tumor aggressiveness through the production of amino-sugar/nucleotide sugar products. Accumulation of these products facilitates the abnormal glycosylation of cancer cells, often leading to inhibition of the immune process. Thus, targeting aberrant glycosylation may synergize with immune checkpoint blockers to improve therapeutic efficacy. To identify gene(s) critical for survival of human non-small cell lung cancer (NSCLC) with KRAS/LKB1 co- mutations (KL), a highly aggressive molecular subtype of NSCLC, compared to those with KRAS mutations (K), we performed a genome-wide CRISPR knockout screening using an isogenic pair of K cells with or without LKB1 loss. Based on integrative analysis using MAGeCK ranking algorithms and subsequent validation assays, a gene encoding ALG5 dolichyl-phosphate beta-glucosyltransferase (ALG5) in the N-glycosylation biosynthesis pathway emerged as the top candidate responsible for KL NSCLC survival and proliferation. By establishing both molecular and metabolic platforms to measure metabolites and glycan species involved in KL proliferation, and utilizing clinically relevant mouse models for in vivo studies, we are now poised to define the oncogenic role of ALG5 during lung tumorigenesis and aggressiveness. In Aim 1, we will interrogate the mechanistic basis of ALG5 dependence in KL NSCLC cells. In Aim 2, we will investigate the molecular mechanism by which LKB1 regulates ALG5. In Aim 3, we will examine 1) whether ALG5 suppression reduces tumor growth in vivo and 2) whether ALG5 suppression-mediated alteration in N- glycans can perturb tumor cell-immune cell interaction, enhancing immune cell infiltration and create ‘immune- hot’ conditions. While the role of O-GlcNAcylation in cancer growth, another arm downstream of amino- sugar/nucleotide sugar metabolism pathway, has been reported, the importance of N-glycosylation metabolism in KL NSCLC has yet to be elucidated. By combining cell biology, state-of-the art glycan mapping techniques, spatial single cell transcriptomics and in vivo studies, this work will provide comprehensive insight into the vulnerability of KL NSCLC tumors to inhibition of ALG5 and potentially illuminate novel and selective treatment strategies.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY / ABSTRACT Obesity is a leading cause for primary hypertension, with >70% of the cases are estimated to be associated with elevated BMI. Chronic overnutrition alters brain circuits with the help of elevated adipose hormone leptin, causing increased sympathetic outflow and blood pressure (BP). Hypothalamic inflammation is a major hallmark of obese brain and abundantly contains features like reactive astrogliosis. Astrocytes are an integral part of leptin responsive circuits; they express leptin receptors and morphologically interact with melanocortin pathway neurons. Moreover, impairing leptin receptor signaling or inflammation selectively in astrocytes is sufficient to protect against hypertension, suggesting that obesity induced astrocytic adaptations play causal role in cardiovascular sequela. However, how overnutrition and subsequent inflammation change key astrocytic intracellular activity of Ca2+ and cAMP in vivo remains elusive. This is an important knowledge gap given the established functional roles played by these signaling molecules. Additionally, how astrocytic activity affects neighboring leptin responsive neurons in normal and obese states is unknown. Using in vivo fiber photometry imaging, we found that hypothalamic astrocytes display spontaneous Ca2+ waves. To understand its functional role, we used chemogenetics (hM3Dq) to increase Ca2+ and found that stimulating mediobasal hypothalamic astrocytes increased AgRP neuron activity and reduced renal sympathetic activity (rSNA). Importantly, leptin suppressed the baseline Ca2+ waves in astrocytes. Based on these findings, we hypothesized that tonic Ca2+ activity in astrocytes stimulates AgRP neurons to inhibit melanocortin pathway and acts as a brake on autonomic output. Suppression of this activity by elevated leptin, as seen in obesity, removes astrocytic brakes on sympathetic outflow and drives hypertension. Here we will test this hypothesis with the following complementary goals: aim 1 will use chemogenetics to modulate astrocytic Ca2+ and cAMP levels to uncover precise nature of interaction between astrocytic activity and rSNA, BP and heart rate (HR). Using in vivo fiber photometry, we will also monitor astrocytes’ impact on the activity of melanocortin pathway neurons (AgRP, POMC and MC4R), which mediates leptin induced hypertension. Aim 2 will determine how high fat diet induced obesity alters Ca2+ and cAMP dynamics in hypothalamic astrocytes in vivo and whether chemogenetically restoring this activity is sufficient to ameliorate hypertension. Collectively, these two aims will uniquely bring together expertise from two laboratories specialized on hypothalamic circuits of energy homeostasis and cardiovascular regulation. By employing a set of state-of-the-art approaches, successful completion of these aims will provide unprecedented insights into the mechanism(s) by which astrocytes contribute to obesity induced hypertension. Ultimately, these studies will likely provide novel therapeutic targets by unveiling the untapped potential of astrocytes for antihypertensive medicine.

NIA - National Institute on Aging

PROJECT SUMMARY: Most people living with HIV (PWH) experience premature aging and a reduced healthspan, even while on antiretroviral therapy (ART). However, a unique group of PWH, termed “SuperAgers,” defy these trends, maintaining exceptional healthspan and resilience against aging-associated comorbidities. These individuals provide a unique opportunity to uncover novel mechanisms of healthy aging in PWH. In our recent publication, we found that PWH on ART exhibit elevated levels of senescence-associated glycan- degrading enzymes. These enzymes, namely β-galactosidase and sialidase, degrade the anti-inflammatory glycans, galactose and sialic acid, on circulating glycoproteins. This degradation disrupts anti-inflammatory pathways that normally inhibit excessive NF-κB signaling, to protect against virus-induced inflammation. Consistently, this glycan degradation in PWH correlates with increased inflammation, accelerated biological aging, and a higher prevalence of comorbidities. The therapeutic potential of targeting this mechanism was evident when we inhibited these glycan-degrading enzymes in a humanized mouse model of viremic HIV infection: anti-inflammatory glycans were preserved and both inflammation and biological aging were reduced. While preventing glycan degradation reduces HIV-associated inflammation, a more comprehensive strategy may involve targeting senescent cells directly to mitigate all deleterious consequences of their accumulation. We recently found that accelerated biological age in PWH on ART correlates with elevated expression of urokinase plasminogen activator surface receptor (uPAR), a marker highly expressed on senescent cells. Preclinical studies have shown that targeting uPAR⁺ cells is safe and can selectively eliminate senescent cells and improve healthspan in animal models. However, this approach has not yet been explored in the context of HIV. Together, these findings support our overarching hypothesis: senescence-associated mechanisms, including glycan-degrading enzymes and uPAR overexpression, contribute to inflammaging and premature aging in PWH, are mitigated in SuperAgers, and can be targeted to reduce inflammaging in the context of HIV. We propose two specific aims to address this hypothesis: Aim 1 will determine whether healthy aging during HIV infection is associated with low levels of glycan-degrading enzymes and uPAR, using longitudinal samples from older PWH spanning an aging phenotype gradient, from SuperAgers to individuals with aging-related comorbidities such as cognitive impairment and frailty. Aim 2 will assess whether targeting glycan-degrading enzymes and uPAR can reduce premature aging and inflammaging during ART-suppressed HIV infection using a non-fetal tissue-based humanized mouse model. Together, this study aims to elucidate novel senescence- associated mechanisms that contribute to premature aging in PWH on ART. By targeting uPAR and glycan- degrading enzymes, we also aim to uncover actionable pathways that could inform new therapies to extend healthspan and reduce age-related complications in PWH.

NIDA - National Institute on Drug Abuse

Project Summary Opioid misuse remains an unrelenting epidemic, and, while widespread use of naloxone saves lives by acutely reversing the short-term effects of opioid overdose, therapeutic options for mitigating the debilitating complications from non-fatal opioid overdose (NFOO) are entirely lacking. Respiratory suppression and subsequent hypoxia are the primary causes of adverse health effects seen in NFOO, which include kidney failure, heart complications, seizures, nerve damage, and particularly brain injury resulting in impaired cognitive, affective, and motor function. Evidently, the histone methyltransferase G9a is a key mediator of hypoxia-induced damage in tissues by suppressing genes critical to protecting against oxidative damage, fibrosis, inflammation, and apoptosis. Specifically, animal studies demonstrate G9a inhibition to be protective in many hypoxia models, including stroke, myocardial infarction, and ischemia/reperfusion, implicating the mechanistic role of G9a activity in NFOO-induced hypoxia-related pathogenesis. Recently, we made a breakthrough discovery identifying a G9a- mediated translation mechanism driving neuropathogenesis in Alzheimer’s Disease (AD). Based on this mechanistic discovery we developed and characterized MS1262, a novel, potent, brain-penetrant inhibitor of G9a, as an effective drug for AD therapeutics. Here, by targeting G9a and G9a-mediated translation mechanisms we will develop a similar therapeutics strategy for improving NFOO health outcomes. TransChromix, a startup company created by the NC Kick-Start program, and Professor Xian Chen at the UNC School of Medicine, will conduct this project. MS1262 treatment in three different AD mouse models rescues cognitive and affective function, as well as improves neuroinflammation and synaptic dysfunction, which are hallmarks of brain injury seen in NFOO. Notably, no adverse effects have been observed in these models. Strikingly, in our comparative proteomic and phosphoproteomic analysis of hippocampi from mice receiving acute fentanyl injection with versus without MS1262 treatment, we found that G9a inhibition broadly affected a series of the pathways related to hypoxia- impaired synaptic function and neuronal damage. Using two models of hypoxic stress, including fentanyl injection and hypobaric chambers, we will test the hypothesis that MS1262 treatment will (1) Mitigate hypoxia induced tissue damage and (2) Prevent cognitive, affective, and motor impairments. Furthermore, we will use our state- of-the-art multiomics approaches to identify mouse-to-human conserved mechanisms of NFOO complications rescued by MS1262, thus mechanistically deriving new biomarkers for companion diagnosis of treatment effects that having promising human potential. In Phase II we will use the Phase I-optimized doses with low toxicity to test the treatment efficacy for NFOO complications. Meanwhile, we will develop companion diagnostic assays to stratify individuals for enhanced therapy with high response rates. The end deliverable of phase II funding will be an FDA IND application.

NCI - National Cancer Institute

PROJECT SUMMARY/ABSTRACT CANDIDATE: As a postdoctoral fellow in Dr. Scott Lowe’s lab at Memorial Sloan Kettering Cancer Center (MSKCC), my research has focused on the impact of aberrant cell surface remodeling on CAR T cell therapy and immune evasion. My long-term goal is to establish an independent research program aimed at discovering new cancer cell-specific surface antigens for cell therapy and understanding mechanisms of resistance to immunotherapy. The proposed research will lay a solid foundation for establishing my own research group by the end of the mentored phase of this award. To ensure my successful transition to independence, I have developed a detailed training plan focusing on four key areas: (1) scientific and career mentorship; (2) expansion of knowledge and skills; (3) professional development; and (4) transition to independence. RESEARCH: Cancer progression involves extensive cell surface remodeling that enables immune evasion but also exposes therapeutic vulnerabilities. However, how these dynamic surface changes shape tumor–immune interactions and fibrosis remains poorly understood. My postdoctoral work has established a novel cell surface proteomics and labeling pipeline that systematically maps the tumor surface proteome across multiple cancer types. This approach identified the urokinase plasminogen activator receptor (uPAR) as a conserved, senescence- and fibrosis-associated antigen enriched in p53-mutant tumors. Using advanced mouse models and a state-of-the-art CAR T cell engineering platform, I developed uPAR-directed CAR T cells that show potent anti-tumor activity with minimal toxicity. Building upon these findings, my proposed research seeks to define and therapeutically exploit senescence- and fibrosis-associated tumor states as new classes of immunotherapy targets. In Aim 1, I will investigate how therapy-induced senescence enhances uPAR CAR T cell activity and develop next-generation CAR designs with improved potency and safety. In Aim 2, I will target tumor-associated fibrosis by eliminating uPAR⁺ fibroblasts and myeloid cells that sustain immunosuppression, and develop dual-targeting strategies to coordinate tumor and stromal clearance. Together, these studies will elucidate how pathological surface remodeling during senescence and fibrosis creates actionable immune targets, establishing a foundation for engineered cell therapies that overcome antigen heterogeneity and fibrotic immune barriers in solid tumors. Vertebrate animal models are necessary to evaluate the antitumor efficacy, safety, tissue trafficking, and immune effects of uPAR-directed CAR T-cell therapies within an intact tumor microenvironment. These complex interactions among tumor, stromal, immune, and normal-tissue compartments, as well as longitudinal therapeutic responses and potential toxicities, cannot be adequately reproduced using in vitro systems alone. ENVIRONMENT: MSKCC provides an ideal environment for me to accomplish my training and research goals, and successfully transition to an independent faculty position at an academic institution. My mentor Dr. Lowe is a world leader in cancer biology, with a particular expertise on senescence, tumor suppressor networks, mouse models, and functional genetics. My co-mentor Dr. Sadelain is a world leader in CAR T cell engineering and therapy. In addition, I have assembled an advisory committee of three established scientists with relevant expertise and strong commitment to mentoring (Drs. Shah, Li, and Zamarin), who will support my transition to independence by providing valuable research and career guidance. Combined with the collaborative environment and rich resources at MSKCC, this support network creates optimal conditions for the successful completion of the proposed research and career development plans.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY The persistence of Human Immunodeficiency Virus (HIV) in long-lived latent reservoirs remains one of the major barriers to a functional cure. The latent reservoir consists of cells harboring replication-competent, but transcriptionally inhibited proviruses that evade immune clearance even in patients on long-term antiretroviral therapy (ART). Spontaneous reactivation of these proviruses results in viral rebound upon treatment cessation, thus mandating life-long treatment. Furthermore, the production of viral transcripts and antigens from these cells, even in the absence of productive infection, is thought to contribute to persistent inflammation and increased rates of co-morbidities among people with HIV (PWH). Therefore, the development of small molecule regulators of viral transcription as ART adjuvants to reign in chronic inflammation and/or to manage the reservoir en route to a functional cure remains an NIH HIV/AIDS high priority research topic. The licensing of transcriptional elongation by the cyclin-dependent kinase complex known as P-TEFb is one of the most heavily regulated steps in mammalian gene expression. P-TEFb is normally recruited to sites of nascent transcription by a series of context-dependent complexes, including transcription factors, epigenetic regulators, and super elongation complexes (SECs). HIV-1 circumvents this regulatory step through its viral Tat protein, which directly recruits P- TEFb to sites of nascent proviral transcription through recognition of the TAR RNA stem loop produced at the 5’ end of viral RNA transcripts. Biochemical purifications of Tat have found that it also binds a specific cellular SEC, which has been shown to facilitate viral transcription in some cell line models. However, we recently found that this SEC is dispensable for viral replication in primary CD4+ T cells. To validate this finding, we characterized a series of small molecule SEC inhibitors (iSECs) that block the interaction of P-TEFb with these SEC complexes. Treatment of primary CD4+ T cells with iSECs increased viral replication and viral transcript production, suggesting that the SEC is not only dispensable for viral replication, but that it may serve as a reservoir for P- TEFb release. Several small molecules that enhance the availability of P-TEFb (e.g., BRD4 inhibitors) have been shown to stimulate viral transcription and reactivation from latency. Indeed, we found that iSECs synergize with latency reversing agents to enhance viral transcription in peripheral blood mononuclear cells from PWH on suppressive ART. Based on our preliminary data showing that the SEC is not required for viral transcription in primary CD4+ T cells and that it can be targeted as a reservoir of P-TEFb by iSECs for latency reversal, here we seek to address three critical questions: 1) What P-TEFb-containing complex is required for HIV transcription in primary CD4+ T cells?; 2) Does HIV use the SEC in other cellular contexts?; and 3) What is the potential of iSECs as latency reversing agents compared to other P-TEFb release strategies? Ultimately, these studies will clarify the transcriptional elongation complexes that regulate HIV replication and latency towards the development of next-generation ART adjuvants designed to manage the reservoir.

NHLBI - National Heart Lung and Blood Institute

Project Summary Dilated cardiomyopathy (DCM) is a common cause of heart failure with a severe lack of therapeutics, creating a significant clinical burden. The gene TRAPPC11 emerged from a whole transcriptome, functional screen for therapeutic targets for DCM using patient-derived human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), demonstrating reversion of contractile dysfunction upon knockdown in DCM hiPSC-CMs. TRAPPC11 is a modulator of endoplasmic reticulum (ER) stress. Since ER stress is recognized as a pathophysiological driver in DCM, my overarching hypothesis is that inhibition of TRAPPC11 would be therapeutic for DCM caused by TNNT2 mutations and possibly more broadly for other forms of DCM. This hypothesis will be tested through knockdown of TRAPPC11 in a mouse model of TNNT2 DCM and in myofilament and nonmyofilament induced DCM in hiPSC-CMs. Interestingly, single nucleotide polymorphisms (SNPs) in TRAPPC11 are associated with left ventricular hypertrophy (LVH) in response to pressure overload in African Americans. Therefore, my secondary hypothesis is that common mechanisms underlie TRAPPC11’s effect on hypertrophy induction and its therapeutic potential for DCM. Using CRISPR/Cas9 genome editing, I will test the effects of TRAPPC11 SNPs associated with LVH on ER/SR function in healthy hiPSC-CMs and introduce key SNPs into DCM hiPSC-CMs to assess their protective potential. Completion of this study will establish a translational and mechanistic rationale for targeting TRAPPC11 in DCM, and might warrant monitoring clinical outcomes of people carrying these SNPs for evidence supporting translatability of targeting TRAPPC11 to treat DCM. The training program proposed in this fellowship application was created to support my potential to become an independent investigator in the future. It will take place in the highly supportive, rich academic environment of Stanford University, where I will have access to state-of-the-art facilities and the opportunity to interact with leading cardiovascular researchers. The plan encompasses scientific technical skills, professional development skills, and both written and oral communication skills and will prepare me for writing my career development award.

Tasveer

Tasveer will organize a Hip Hop workshop for South Asian young adults that will help them learn the history and art of Hip Hop, a form of expression. The workshop will teach the origins of Hip Hop culture in the Black community and how it has come to be one of the most important and defining elements of American pop culture. It will also help participants understand how Hip Hop connects to certain South Asian artistic styles, culture, and performance both currently and historically. The workshop will be presented online and be completed by September 30, 2020.

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