Date of Award

2020

Document Type

Thesis

Degree Name

Master of Biomedical Science

Department

Regenerative Medicine and Cell Biology

College

College of Graduate Studies

First Advisor

Russell (Chip) Norris

Second Advisor

Laura Kasman

Third Advisor

Antonis Kourtidis

Fourth Advisor

Steven W. Kubalak

Fifth Advisor

Robin C. Muise-Helmericks

Abstract

Mitral valve prolapse (MVP) is one of the most common forms of cardiac valve disease and affects 1 in 40 individuals worldwide. MVP can lead to arrhythmias, heart failure, and sudden cardiac death and 1 in 10 patients will require valve surgery. Surgery for MVP is now the fastest growing cardiovascular intervention in the Western world. As such, MVP carries a significant burden of morbidity and mortality. Our lab was the first to identify a cause for non-syndromic MVP using a combination of linkage analyses, as well as capture sequence of the linkage interval, to identify loss of function mutations in the cadherin gene, DCHS1. Two-hybrid screens were undertaken to further understand DCHS1 function and the RNA binding protein, LIX1L was identified as the only interacting protein. LIX1L binds and promotes miRNA processing through interactions as an RNA-binding protein and miRNAs. This leads us to the hypothesis: DCHS1-regulated miRNA processing stabilizes the valve endocardium. Expression studies have corroborated this theory as DCHS1, LIX1L, and the microprocessor proteins are expressed in endothelial cells in the mitral valve. Cell culture data shows that a loss of DCHS1 compromises processing of target miRNAs through the microprocessor leading to a significant decrease in miRNA expression. Expression studies have also shown that loss of Dchs1 reduces valve endocardial stability, which may be caused by the loss of miRNAs. These studies illustrate the importance of DCHS1 effects on valve endocardium stabilization in MVP. Uncovering how these changes lead to clinically significant pathology later in life is crucial to the characterization of MV.

Rights

All rights reserved. Copyright is held by the author.

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