Publication Date



Open access

Embargo Period


Degree Type


Degree Name

Doctor of Philosophy (PHD)


Molecular and Cellular Pharmacology (Medicine)

Date of Defense


First Committee Member

Joy Lincoln

Second Committee Member

Nanette H. Bishopric

Third Committee Member

Steven E. Lipshultz

Fourth Committee Member

Mary Lou King

Fifth Committee Member

Lidia Kos


Heart valve structures open and close during the cardiac cycle to provide unidirectional blood flow through the heart, critical for efficient cardiovascular function. Valve dysfunction results in either incomplete opening or incomplete closure of the valve. Both types of valve dysfunction decrease efficiency of blood flow, increasing the load on the myocardium and leading to secondary heart disease such as pathological hypertrophy and heart failure. There are currently no effective treatments to prevent or slow the progression of valve disease, and there are no pharmacological treatments for advanced valve disease. Although most valve disease is associated with aging, increasing evidence suggests that valve disease often has origins in development. Congenital valvuloseptal defects affect many newborns, ranging from life-threatening malformations requiring immediate repair to more subtle, often undiagnosed defects that increase susceptibility to valve disease later in life. Therefore, an improved understanding of the mechanisms of heart valve formation and maintenance of adult valves may serve as an important step in improving valve disease treatment options. In this work, the mechanisms of normal valve development and the role of Sox9 in developing and mature valves are further studied. The temporal and spatial expression of extracellular matrix genes and proteins are examined throughout normal murine valve development. Sox9 function in the processes of valve development and valve maintenance is examined using mouse models of conditional Sox9 loss-of-function. Heart valve phenotypes in mice with reduced Sox9 function are examined throughout development and in adult mice with resultant calcific valve disease. The possible causative mechanisms of calcific valve disease in mice with reduced Sox9 function are further investigated by identification of novel possible targets of Sox9 transcriptional regulation. Together these studies improve our understanding of heart valve development, characterize a model of heart valve calcification with genetic etiology, and identify and characterize novel targets of Sox9.


Sox9; transcription factor; heart valves; development; valve calcification