Date of Award

2021

Embargo Period

7-27-2023

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Regenerative Medicine and Cell Biology

College

College of Graduate Studies

First Advisor

Russell "Chip" Norris

Second Advisor

Robin Muise-Helmericks

Third Advisor

Antonis Kourtidis

Fourth Advisor

Jeffrey Jones

Fifth Advisor

Michael Ostrowski

Abstract

Cardiac valve diseases are serious heart conditions and present a significant burden on human health by affecting 2.5% of the population. Mitral Valve Prolapse (MVP) is one of the most common forms of valve disease and progression of it results in complications such as blood regurgitation, arrhythmia, and sudden cardiac death. Nonsurgical treatments for MVP do not exist and therapeutic development has been hindered by incomplete understanding of disease etiology. Recent studies from our lab and others have emphasized the inheritance and developmental basis of MVP through the identification of several causal genes. Familial and GWAS studies in humans potentiated the discovery of candidates including primary cilia gene, DZIP1 and cytoskeleton associated genes such as Dachsous Cadherin Related-1, DCHS1. With genetically accurate mouse models, we have illustrated their function in valve disease and have begun to define mechanisms that explain disease inception during critical developmental timepoints. Studies performed through this dissertation were aimed to advance our understanding of molecular mechanisms that are associated with primary cilia and mediated by DCHS1. First, the expression and function of platelet-derived growth factor (PDGF) signaling through cilia specific receptor, PDGFRα, was investigated. Immunofluorescence staining revealed a unique expression profile of PDGFRα in the valve endothelium and motivated the conditional ablation Pdgfra in a subset of endothelial cells in mice. Our data suggest that PDGFRα contributes to valvulogenesis by stabilizing endothelial-mesenchymal transition, independently of primary cilia. Additional studies investigated DCHS1-based mechanisms and through proteomic and biochemical approaches, identified novel protein interactors including cytoplasmic proteins, Lix-1 Like (LIX1L) and Septin-9 (SEPT9). Perturbation of the DCHS1-LIX1L-SEPT9 protein complex in vivo and in vitro characterized the interaction with and regulation of the actin cytoskeleton during valvulogenesis. Together, these findings elucidate mechano-biochemical cues of MVP disease inception and thus, highlight the complex and critical homeostasis of developing valve tissues.

Rights

All rights reserved. Copyright is held by the author.

Download

Share

COinS