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New Britain Museum of American Art

Survey and Planning

Swarovski Foundation

Funds creative arts, culture, and environmental conservation through luxury philanthropy.

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.

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.

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>

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.

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.

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.

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.

LANGUAGE LINE SOLUTIONS

Editorial and Design and Graphic and Fine Art Services

LANGUAGE LINE SOLUTIONS

Editorial and Design and Graphic and Fine Art Services-Writing and translations-In person language interpretation services

NIA - National Institute on Aging

Extreme weather events pose major risks for population health and mortality, particularly for incarcerated people who have limited control over their thermal environments. Several aspects of the prison built environment (such as overcrowding, insufficient heating or air-conditioning, and heat-retaining building materials) likely worsen extreme temperature exposure, yet there has been no comprehensive investigation of the health consequences of extreme temperature exposure inside US prisons. Research on non-institutionalized populations has established extreme heat and cold temperature exposures as acute contributors to cardiovascular and respiratory disease mortality, which are leading causes of death among the 1.2 million people imprisoned in the U.S. (and among the leading causes of death in incarcerated people over the age of 55, the fastest growing cohort in U.S. prisons today). This project’s overall objective is to assess extreme indoor prison temperatures in relation to mortality among incarcerated adults in the U.S. and identify prison conditions and policies that prevent these harms. Aim 1 will use state-of-the-art building science methods and leverage a unique database of prison conditions to develop the first estimates of daily indoor temperatures for facilities in the 20 largest state prison systems, including over 600 prisons and 800,000 imprisoned adults, representing over three quarters of the imprisoned adult population. Indoor temperature and humidity estimates and prison policy and conditions data will be linked with the latest data from Mortality in Correctional Institutions to examine associations with excess all-cause cardiovascular and respiratory disease mortality in prisons. Aim 2 will evaluate prison overcrowding and lack of air-conditioning as factors that may elevate risk for temperature-related mortality. Aim 3 will apply legal epidemiologic methods to develop a comprehensive database of temperature safety strategies and examine relationships with temperature-related mortality in prisons.

Tennessee Arts Commission

Tennessee Arts Commission provides grants to support arts and cultural programming, artist fellowships, arts education, and community-based arts projects across TN.

Tennessee Arts Commission

Arts Education project grants support artist residencies, arts integration projects, and creative learning initiatives in Tennessee schools, fostering student engagement and academic achievement through arts-based instruction.

Tennessee Arts Commission

The Tennessee Arts Commission provides general operating support to established arts organizations across the state, enabling sustained programming in visual arts, performing arts, literary arts, and multidisciplinary arts.

Tet in Seattle

Tet in Seattle will organize the annual Tet in Seattle Festival, a free event that celebrates the cultural roots of Vietnamese Americans through recognizing the Lunar New Year. The two- day festival will be held Saturday, January 18, and Sunday January 19, 2020 from 11am to 6pm at Seattle Center (305 Harrison St). It will feature a health fair, art, music, entertainment, and foods that are unique to the Vietnamese Community.

Texas Commission on the Arts

Texas Commission on the Arts provides grants to support arts and cultural programming, artist fellowships, arts education, and community-based arts projects across TX.

Texas Commission on the Arts

Supports the creation and presentation of excellence in the arts through grant programs for arts organizations, artists, and communities across Texas.