Familial cardiomyopathies are the leading cause of sudden death in people under 30. Two closely related cardiomyopathies, hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are characterized by remodeling of the tissue in the ventricular wall, often accompanied by fibrosis, and myocyte disarray. These diseases are primarily caused by mutation of the proteins involved in generating or regulating power output by the heart. It has been proposed that HCM is caused by hypercontractility at the molecular level while DCM is caused by hypocontractility at the molecular level; however, it is not clear how mutations at the molecular level lead to alterations in the contractility and structure of heart cells and tissues. The goal of this research is to better understand the connections between molecular-based changes and the changes in contractility and structure at the cellular and tissue levels. To do this, we will harness biophysical, biochemical, cell biological, and tissue engineering techniques to measure contractility across these scales of organization, and then use mathematical modeling to connect these observations. We will examine two model mutations in troponin-T that cause either HCM or DCM.
In Aim 1, we will dissect the molecular mechanism of two mutations in cardiac troponin-T, R92Q and ?K210, that cause hypercontractility and hypocontractility at the molecular level, respectively.
In Aim 2, we will dissect the effects of these mutations on the structural and contractile properties of stem cell derived cardiomyocytes and engineered tissues.
In Aim 3, we will examine whether these mutations affect the ability of cells and tissues to sense and respond to their mechanical environment. This bottom up approach will give unprecedented insights into the mechanisms of cardiac force production, mechanosensing by the heart, and the disease pathogenesis of familial cardiomyopathies.

Public Health Relevance

Familial cardiomyopathies are the leading cause of sudden death in people under 30 and they are found in up to 1:500 people in the population. While many of the mutations that cause the disease have been identified, how these mutations lead to the disease is not well understood. Our research will give unprecedented insights into heart function and familial cardiomyopathies, setting the foundation for the development of new treatments for these heart diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL141086-02
Application #
9677069
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Tjurmina, Olga A
Project Start
2018-04-01
Project End
2023-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Washington University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130