Author ORCID Identifier

0000-0001-5510-7356

Date of Graduation

8-2019

Document Type

Dissertation (PhD)

Program Affiliation

Biochemistry and Molecular Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Harry Karmouty-Quintana, Ph.D.

Committee Member

Darren F. Boehning, Ph.D

Committee Member

Seyed J. Moghaddam, M.D.

Committee Member

Ann-Bin Shyu, Ph.D.

Committee Member

Ambro van Hoof, Ph.D.

Committee Member

Yang Xia, M.D. Ph.D.

Abstract

Pulmonary hypertension (PH) is a progressive disease with serious effects on quality of life and life expectancy of patients. PH is a complex disease that likely develops due to multiple influences, and no curative treatments exist for this disease. It has been shown that alternative polyadenylation (APA) due to depletion of Nudix Hydrolase 21(NUDT21) is involved in several disease states including the chronic lung disease idiopathic pulmonary fibrosis (IPF). Additionally, hyaluronan, an extracellular matrix glycosaminoglycan has been associated with PH. The role and mechanism of NUDT21 and hyaluronan have not yet been described in this disease. My results reveal that NUDT21 depletion and APA in pulmonary artery smooth muscle cells (PASMCs) is associated with phenotypic changes and PH. I I also show that hyaluronan and hyaluronan related genes play important roles in the development of Pulmonary Arterial Hypertension (PAH) and PH associated with IPF and combined pulmonary fibrosis and emphysema. I also identify 4-methylumbelliferone as an inhibitor of PH in this mechanism. These studies provide new mechanisms for understanding the development of PH and potential therapeutic targets.

Keywords

Pulmonary Hypertension, Alternative Polyadenylation, APA, Hyaluronan, HAS2, Combined Pulmonary Fibrosis and Emphysema, CPFE, HA

Available for download on Monday, February 10, 2020

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