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