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Tachycardia-induced Metabolic Remodeling Drives Cardiac Dysfunction

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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.

Up to $249K
2029-01-31
health research

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

Tactical Behaviors for Autonomous Maneuver

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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&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.

$100K – $2.3M
rolling
sciencetechnology

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

Targeting TRAPPC11 as a therapeutic in inherited dilated cardiomyopathy

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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.

Up to $75K
Rolling
health research

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

Temperature-Related Mortality in U.S. State Prisons

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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.

Up to $560K
2031-01-31
health research

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

Thailand HIV/AIDS and Infectious Disease Clinical Trials Unit (THAI CTU)

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NIAID - National Institute of Allergy and Infectious Diseases

Thailand HIV/AIDS and Infectious Disease Clinical Trials Unit (THAI CTU) SF 424 (R&R) Other Project Information – Project Summary The Thailand HIV/AIDS and Infectious Disease Clinical Trials Unit (THAI CTU), current NIAID CRMS site 60338, is a collaboration between the Chiang Mai University-Research Institute for Health Sciences (CMU- RIHES) in Chiang Mai, Thailand, and the Thai Red Cross AIDS Research Centre (TRC-ARC) in Bangkok, Thailand. The specific aims of this application are 1) to renew the THAI CTU as a Clinical Trials Unit to provide scientific, administrative expertise, and infrastructure to conduct clinical studies developed by the four NIH HIV/AIDS Clinical Trials Networks: HIV/AIDS Adult Therapeutics, HIV/AIDS Maternal, Adolescent and Pediatric Therapeutics, HIV Prevention, and HIV Vaccines; and 2) to participate in the development of clinical trials and provide four Clinical Research Sites (CRS) to conduct clinical trials proposed by the four Networks. This CTU renewal involves a change of THAI CTU Principal Investigators from "Suwat Chariyalertsak and Kiat Ruxrungtham" to “Khuanchai Supparatpinyo and Kiat Ruxrungtham". The THAI CTU and its four CRSs will contribute scientifically to the Networks and recruit HIV+ and HIV- participants to clinical studies according to HIV/AIDS research priorities: 1) HIV/AIDS adult therapeutics: 1) interventions to reduce HIV reservoirs; 2) novel and durable interventions targeting HIV treatment; 3) treatment and prevention of drug-sensitive and drug-resistant tuberculosis; 4) treatment and prevention of HIV-related, non-infectious co-morbidities; and 5) studied strategies to cure hepatitis B virus infection in people with and without HIV. High national incidence of viral hepatitis and endemicity of carriage facilitates research on HBV and HCV infections, particularly for cure of hepatitis B. 2) HIV/AIDS maternal, adolescent and pediatric therapeutics: 1) optimization of antiretroviral treatment for these populations; 2) interventions for ART-free remission; 3) treatment and prevention of tuberculosis; 4) treatment and prevention of HIV-related co-morbidities; and 5) treatment and prevention of co-infections. 3) HIV prevention: 1) evaluation of long-acting antiretroviral agents and delivery systems for pre- exposure prophylaxis; 2) evaluation of multipurpose prevention technologies for HIV, pregnancy, sexually transmitted infections, and opioid dependence; 3) evaluation of broadly neutralizing antibodies for pre-exposure prophylaxis; and 4) integrated strategies for HIV prevention. 4) HIV vaccines: 1) evaluation of passive immunization to reduce HIV acquisition in adults; 2) investigation of vaccination of infants; 3) evaluation of immunological, microbiological, and diagnostic technologies for TB vaccination; and 4) research on epidemiological, behavioral, and social sciences for optimization of outcomes of HIV vaccination.

Up to $468K
2027-11-30
health research

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

The Child Health Research Career Development Program at UCSF

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NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

Project Summary/Abstract This application is submitted in response to RFA-HD-18-011, Child Health Research Career Development Award (CHRCDA) Program to provide K12 awards through the CHRCDA mechanism to young pediatric investigators. This new application requests resources to support three pediatricians each year who hold MD or MD/PhD degrees and have completed scholarship training in a clinical subspecialty. The rationale for the program is based on the well-documented and urgent need to support mentored career development for pediatricians to enable them to become fully independent and productive basic science researchers, and the fact that the department of Pediatrics at UCSF has the vision, experience and infrastructure to train the next generation of leaders in pediatric science. Our aims are to (1) offer a structured program for training academic pediatricians, (2) foster career development and promote retention of junior faculty, (3) expose promising early career pediatricians to the intellectual richness of UCSF research and (4) promote diversity in academic pediatrics. The scholars trained by this program will bring state-of-the-art approaches to bear on diagnosis, treatment and prevention of health problems in children as well as childhood onset of adult illness. The design of this program involves harnessing the expertise of world- class basic laboratory scientists who will serve as mentors for interdisciplinary training. The basic science training program is focused around eight scientific cores: cancer, cardiopulmonary medicine, developmental biology, genetics, immunology, neurobiology, stem cell biology, and our new computational sciences core. Each core has a Director, designated faculty, and a specific didactic curriculum. The scholars, in conjunction with their mentor and Core Director, will also participate in a program of additional discipline-specific course work dependent on both the prior experience and training of the applicant and the scientific theme of the trainee’s research, which may often overlap amongst different cores. In this application, we provide evidence that the Department of Pediatrics together with the broader UCSF research community comprise an exceptional environment for preparing young pediatricians who will receive support through the CHRCDA mechanism for successful careers as basic science researchers. There are > 1,200 research laboratories and > 2,200 active research projects at UCSF, and the faculty includes 5 Nobel laureates, 64 members of the American Academy of Arts and Sciences, 76 members of the Institute of Medicine, and 18 Howard Hughes Medical Institute investigators. This program is an investment in the future of children's health, as the diverse group of researchers we will train will harness advanced research strategies to address urgent problems that will result in new treatments to improve child health.

Up to $445K
2027-03-31
health research

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

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