02/05/2024
By Irma Silva

The Kennedy College of Sciences, Department of Biological Sciences, invites you to attend an Master’s thesis proposal defense by Alyssa Kennedy entitled, "The Role of Troponin-Tropomyosin Electrostatic Interactions in Cardiac Thin Filament Regulation."

Candidate: Alyssa Kennedy
Date: Thursday, Feb. 15, 2024
Time: 2 to 4:30 p.m.
Location: Olsen 103

Committee members:

  • Jeffrey Moore, Professor, Biological Sciences, University of Massachusetts Lowell
  • Nicolai Konow, Assist. Professor, Biological Sciences, University of Massachusetts Lowell
  • Matthew Gage, Assoc. Professor, Chemistry, University of Massachusetts Lowell

Title: "The Role of Troponin-Tropomyosin Electrostatic Interactions in Cardiac Thin Filament Regulation"

Abstract:
Hypertrophic Cardiomyopathy (HCM) is a dominant genetic heart disease that affects 1 in 500 people. Despite this high prevalence, the situation is much more dire because the disease has variable penetrance and is often asymptomatic until presenting itself in adolescence or adulthood as sudden death. Currently, families of individuals who are diagnosed with HCM and express a known disease-linked mutation are recommended for genetic counseling and appropriate follow-up. However, over ~50% of HCM cases reveal previously unidentified mutations, which are often called Variants of Unknown Significance (VUS). To determine if these mutations are indeed disease-causing would require extensive and expensive laboratory work that is impractical and not cost effective. The overall goal of this work is to contribute to the development of a new predictive model pipeline that can be used as an efficient, low-cost diagnostic tool. The proposed model leverages recent work by our group and others, which has defined the regulation of heart muscle by calcium at near atomic resolution. Heart function relies on the calcium dependent activation-deactivation of cardiac thin filament, which is critical for its beat-to-beat contraction-relaxation cycles. Recent cryo-electron microscopy experiments by the Namba and Fugii groups have revealed the structural basis for thin filament regulation by calcium. While their findings allowed for a deeper understanding of thin filament regulation by changes in its structure, several parts of the structure were only determined at low resolution leaving residue-residue interactions and their effects unresolved. For example, sarcomeric regulation relies heavily on the specific thin filament structure of the troponin-I (TnI) C-terminus and its binding to tropomyosin (Tpm). However, the structure of this region of troponin and how disease-linked mutations and VUSs may impact the function of this area remain largely unresolved. This gap in knowledge leads to the goal and specific aim of this work to resolve important structurally interacting residues involved in TnI-Tpm interactions. In the proposed work I will determine the importance of electrostatic stabilization of Tpm-TnI interactions in the blocking state by generating charge altering mutations in predicted Tpm-TnI interacting residues. Mutant contractile protein function will be assessed via a microscopic in vitro muscle contraction model system. Results from this proposed research will inform and improve our predictive models of cardiac thin filament regulation and its ability to predict the probability of VUS pathogenicity and potentially inform new therapeutic targets for cardiomyopathies.