R35HL166575
Project Grant
Overview
Grant Description
Mechanical Load Effects on Cardiac Function and Heart Diseases - Significance:
In every heartbeat, cardiac muscle cells generate contractile force to pump blood into circulation against a mechanical load. Cardiomyocytes also sense load changes and adjust the contractility to maintain cardiac output. Excessive overload in pathological conditions leads to heart diseases such as arrhythmias and heart failure. However, fundamental knowledge gaps still exist in the molecular and cellular mechanisms of mechano-transduction in cardiomyocytes, and therapeutic treatments for mechanical stress-associated heart diseases (e.g., hypertension-induced arrhythmias and heart failure, DCM, HFPEF) are severely limited to date.
Innovations:
Previous experiments using load-free cardiomyocytes largely missed mechanical load effects on regulating cardiomyocytes. We will develop an innovative cell-in-gel-TR technology to control mechanical load at the single-cell level. Our studies reveal that the mechanical load on the cell during contraction can feedback to regulate the 3 dynamic systems in excitation-Ca2+ signaling-contraction (E-C) coupling. Closing these feedback loops enables the cardiomyocyte to autoregulate E-C coupling in response to load changes. This conceptual innovation will be explored in our R35 research to understand how mechanical load affects cardiomyocyte function and heart diseases.
Research Plan:
The central theme of my research is to elucidate how the 3 dynamic systems in E-C coupling feedforward and feedback to control the heart function as a dynamically regulated smart pump. In R35, we will expand and deepen our research beyond the 2 R01s to do multi-scale systematic studies of the mechano-transduction mechanisms and functional consequences.
(1) Molecular level study to decipher mechano-chemo-electro-transduction (MCET) pathways, identify the key players, and determine molecular mechanisms.
(2) Cell level study to investigate how mechanical load regulates the dynamic systems of excitation-Ca2+ signaling-contraction coupling.
(3) Heart level study to probe how mechanical load regulates the intact heart function.
(4) Study of heart diseases to understand why/how pathological overload leads to cardiac remodeling, arrhythmias, and heart failure.
These 4 parts are designed to inform and enhance one another to provide a comprehensive view on how mechano-transduction pathways work at the molecular level, integrate at the cell level, and manifest to the heart's ability to autoregulate contractility in response to mechanical load changes in health and diseases.
Capability and Adaptability:
The strength of my research stems from an interdisciplinary approach. The history of my research shows a strong track record in developing new technologies by combining rigorous methods in physics, chemistry, and biology. In R35, I will continue developing innovative solutions and using cutting-edge technologies to achieve the transformative research goals.
Expected Outcome and Impact:
The research outcome will shift the paradigm of cardiac E-C coupling to an autoregulatory model, which will open a new conceptual framework for understanding how mechanical load affects heart diseases and help identify molecular targets for developing new therapies.
In every heartbeat, cardiac muscle cells generate contractile force to pump blood into circulation against a mechanical load. Cardiomyocytes also sense load changes and adjust the contractility to maintain cardiac output. Excessive overload in pathological conditions leads to heart diseases such as arrhythmias and heart failure. However, fundamental knowledge gaps still exist in the molecular and cellular mechanisms of mechano-transduction in cardiomyocytes, and therapeutic treatments for mechanical stress-associated heart diseases (e.g., hypertension-induced arrhythmias and heart failure, DCM, HFPEF) are severely limited to date.
Innovations:
Previous experiments using load-free cardiomyocytes largely missed mechanical load effects on regulating cardiomyocytes. We will develop an innovative cell-in-gel-TR technology to control mechanical load at the single-cell level. Our studies reveal that the mechanical load on the cell during contraction can feedback to regulate the 3 dynamic systems in excitation-Ca2+ signaling-contraction (E-C) coupling. Closing these feedback loops enables the cardiomyocyte to autoregulate E-C coupling in response to load changes. This conceptual innovation will be explored in our R35 research to understand how mechanical load affects cardiomyocyte function and heart diseases.
Research Plan:
The central theme of my research is to elucidate how the 3 dynamic systems in E-C coupling feedforward and feedback to control the heart function as a dynamically regulated smart pump. In R35, we will expand and deepen our research beyond the 2 R01s to do multi-scale systematic studies of the mechano-transduction mechanisms and functional consequences.
(1) Molecular level study to decipher mechano-chemo-electro-transduction (MCET) pathways, identify the key players, and determine molecular mechanisms.
(2) Cell level study to investigate how mechanical load regulates the dynamic systems of excitation-Ca2+ signaling-contraction coupling.
(3) Heart level study to probe how mechanical load regulates the intact heart function.
(4) Study of heart diseases to understand why/how pathological overload leads to cardiac remodeling, arrhythmias, and heart failure.
These 4 parts are designed to inform and enhance one another to provide a comprehensive view on how mechano-transduction pathways work at the molecular level, integrate at the cell level, and manifest to the heart's ability to autoregulate contractility in response to mechanical load changes in health and diseases.
Capability and Adaptability:
The strength of my research stems from an interdisciplinary approach. The history of my research shows a strong track record in developing new technologies by combining rigorous methods in physics, chemistry, and biology. In R35, I will continue developing innovative solutions and using cutting-edge technologies to achieve the transformative research goals.
Expected Outcome and Impact:
The research outcome will shift the paradigm of cardiac E-C coupling to an autoregulatory model, which will open a new conceptual framework for understanding how mechanical load affects heart diseases and help identify molecular targets for developing new therapies.
Awardee
Funding Goals
TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.
Grant Program (CFDA)
Awarding / Funding Agency
Place of Performance
California
United States
Geographic Scope
State-Wide
Related Opportunity
Analysis Notes
Amendment Since initial award the total obligations have increased 50% from $2,203,870 to $3,297,090.
Davis University Of California was awarded
Mechanical Load Effects on Cardiac Function & Diseases - R35 Study
Project Grant R35HL166575
worth $3,297,090
from National Heart Lung and Blood Institute in March 2023 with work to be completed primarily in California United States.
The grant
has a duration of 7 years and
was awarded through assistance program 93.837 Cardiovascular Diseases Research.
The Project Grant was awarded through grant opportunity NHLBI Outstanding Investigator Award (OIA) (R35 Clinical Trial Optional).
Status
(Ongoing)
Last Modified 7/25/25
Period of Performance
3/1/23
Start Date
2/28/30
End Date
Funding Split
$3.3M
Federal Obligation
$0.0
Non-Federal Obligation
$3.3M
Total Obligated
Activity Timeline
Transaction History
Modifications to R35HL166575
Additional Detail
Award ID FAIN
R35HL166575
SAI Number
R35HL166575-3589808247
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Public/State Controlled Institution Of Higher Education
Awarding Office
75NH00 NIH National Heart, Lung, and Blood Institute
Funding Office
75NH00 NIH National Heart, Lung, and Blood Institute
Awardee UEI
TX2DAGQPENZ5
Awardee CAGE
1CBG4
Performance District
CA-90
Senators
Dianne Feinstein
Alejandro Padilla
Alejandro Padilla
Budget Funding
| Federal Account | Budget Subfunction | Object Class | Total | Percentage |
|---|---|---|---|---|
| National Heart, Lung, and Blood Institute, National Institutes of Health, Health and Human Services (075-0872) | Health research and training | Grants, subsidies, and contributions (41.0) | $1,101,935 | 100% |
Modified: 7/25/25