Date of Award

1-1-2022

Embargo Period

4-21-2027

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

Amy Bradshaw

Third Advisor

Carol Feghali-Bostwick

Fourth Advisor

Robin Muise-Helmericks

Fifth Advisor

Michael Yost

Abstract

Collagen is the most abundant protein in the human body and is essential for the structure and function of tissues and organs, including the joints, skin and heart. Collagen assembly and homeostasis can be disrupted in various pathological conditions, including cardiovascular diseases and connective tissue diseases. Mitral valve prolapse (MVP) is a common cardiac valve disease affecting 2.5% of the population. Treatment for MVP is limited to surgical intervention. Reports have indicated that myocardial fibrosis is common in MVP, and many cases of surgical repair go on to have ventricular dysfunction. Analyses of biopsies from patients revealed regionalized LV fibrosis, that was also observed in our MVP mouse model (Dzip1S14R/+). Using this model, we tracked the progression of fibrosis and investigated the roles of inflammation, mechanical strain and mechanosensing primary cilia in the development of fibrosis in MVP. The localization of fibrosis in MVP suggests a response in the papillary and inferobasal myocardium to increased tension from the prolapsing valve and raises an important clinical question about the timeline of surgical intervention in MVP. Contrary to fibrosis, the Ehlers-Danlos Syndromes (EDS) are a group of heritable connective tissue disorders that result in tissue laxity due to changes in collagen genes, or key genes for collagen assembly and function. The hypermobile subtype of EDS (hEDS) is the most common type affecting 1 in 500 individuals. hEDS causes joint hypermobility, musculoskeletal manifestations, and is marked by the presence of several comorbid conditions. The genetic basis of hEDS has remained unknown or lacked a significant understanding of the underlying molecular mechanisms. These studies outline the identification of a novel gene for hEDS, generation of a genetically accurate mouse model, and insights into disease mechanisms and the impact on collagen fibrillogenesis. We have also developed a clinical registry of more than 1,000 individuals with hEDS for additional genetic studies and clinical data collection. hEDS lacks a straightforward diagnostic test and has no direct treatment options, which highlights the need for a better understanding of the genetics and biology of hEDS and comorbidities that will guide development of molecular diagnostic tools and therapies.

Rights

All rights reserved. Copyright is held by the author.

Download

Available for download on Wednesday, April 21, 2027

Share

COinS