Connecting Molecular and Cellular Contractile Dysfunction in Cardiomyopathy

Project Summary/Abstract Cardiomyopathies are major causes of heart failure and sudden death, and they represent a common indicator for heart transplantation. Current therapies have focused on “one-size-fits-all” approaches that improve outcomes in some patients, but not others. Therefore, there is an outstanding need to develop new treatment strategies that improve outcomes for patients. It has been hypothesized that patient outcomes could be improved by taking a precision medicine approach that considers genotype for treating cardiomyopathies; however, it is not clear whether such an approach would be beneficial, and if so, how to best implement this approach. This approach remains unrealized, in part, due to fundamental challenges connecting genotype, phenotype, and treatment options. Here, we will take the critical first steps towards investigating the feasibility of a mechanism-based precision medicine approach by focusing on cardiomyopathy mutations in troponin. Specifically, we will use an innovative combination of biochemical, biophysical, cell biological, and tissue engineering techniques to begin to build a mechanistic understanding of the connections between genotype, molecular and cellular dysfunction, and small molecules that potentially reverse molecular dysfunction for key troponin cardiomyopathy mutations. We have engineered model systems of patient-specific mutations that span from molecules to tissues that enable us to 1) understand the fundamental molecular biophysical mechanisms driving disease pathogenesis for key troponin mutations and 2) probe how molecular dysfunction affects cellular and tissue function in human cells. We will leverage these models to answer the following questions for several key troponin mutations: 1) Is it possible to bin patient mutations into subgroups with common molecular dysfunction? 2) Is it possible to use knowledge of molecular mechanism to identify compounds that reverse the molecular dysfunction of patient-specific mutations? 3) Does reversal of the underlying molecular dysfunction improve cellular and tissue function? The results of these studies will set the stage for the development of new approaches for treating cardiomyopathies.