Date of Award

2018

Embargo Period

8-1-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Regenerative Medicine and Cell Biology

College

College of Graduate Studies

First Advisor

Russell Norris

Second Advisor

Roger Markwald

Third Advisor

Andy Wessels

Fourth Advisor

Joshua Lipschutz

Fifth Advisor

Jay Potts

Abstract

Cardiac valve disease is a major health burden affecting around 5% of the population. Two of the most common cardiac valve disease include mitral valve prolapse (MVP) and bicuspid aortic valve disease (BAV). Currently treatment options consist of invasive surgeries to either repair or replace the damages valve tissues. Evidence suggests that both MVP and BAV are congenital diseases that present complications in patients later in life. Treatment options for these diseases are lacking due to an incomplete understanding of the molecular causes. Mitral valve prolapse (MVP) is one of the most common forms of cardiac valve disease and affects ~2-3% of the human population. MVP can lead to secondary complications such as arrhythmias, heart failure, and sudden cardiac death and 1 in 10 patients will require valve surgery. There are no effective nonsurgical treatments for MVP and therapeutic efforts have been hindered by an incomplete understanding of its fundamental causes. One accessible source of such information may come from genetic studies of MVP. We previously reported familial and GWAS studies that identified genetic mutations and/or excellent candidate targets as causal to MVP. Pathway analyses suggested a common cellular and molecular thread between these studies and invoke the primary cilia as potential unifying mechanism. This discovery is further bolstered by our recent identification of a mutation in a cilia gene in a large family with MVP, DZIP1. Our data show genetic haploinsufficiency of primary cilia in cardiac valves leads to a non-syndromic mitral valve disease in mouse models whereas complete genetic ablation enhances mitral valve phenotype severity and generation of bicuspid aortic valve (BAV). We present, for the first time, a potential common cellular and molecular thread through which MVP and potentially BAV can arise. These studies define the primary cilia as a critical, and previously unrecognized facet of cardiac valve development. Uncovering how valve disease genes regulate downstream signaling cascades will provide key mechanistic insights into MVP and potentially BAV pathogenesis at a cellular and molecular level.

Rights

All rights reserved. Copyright is held by the author.

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