Doctor of Philosophy (PHD)
Molecular and Cellular Pharmacology (Medicine)
Date of Defense
First Committee Member
Lina A. Shehadeh
Second Committee Member
Third Committee Member
Fourth Committee Member
Fifth Committee Member
Cholesterol (C27H46O) is the precursor of steroid hormones, Vitamin D and bile acid and is a key component of the plasma membrane. Cholesterol levels are tightly regulated through biosynthesis, cellular uptake or efflux pathways to remain within a certain range for normal cell survival and function. Disturbed cholesterol homeostasis can be an independent risk factor for human diseases including cardiovascular disease, neurodegenerative disorder and chronic kidney disease. Understanding the molecular mechanisms that govern cholesterol homeostasis has the potential to reveal important insights into disease pathogenesis and new therapeutics. Elevated plasma LDL cholesterol is a major risk factor for cardiovascular events and initiates the built up of atherosclerotic plaque in the arterial wall. In the arterial wall, the accumulated LDL cholesterol reacts with native oxygen species and becomes oxidized LDL that induces inflammatory responses and promote aortic Smooth Muscle Cells (SMCs) to undergo osteoblastic differentiation, proliferate, and hence contribute to the growth of atherosclerotic plaque. The first part of this study identifies microRNA-30e (miR-30e) as an OsteomiR in atherosclerosis. We present evidence that miR-30e regulates a panel of osteogenic genes in bone marrow derived Mesenchymal Stem Cells (MSCs), reduces osteogenic differentiation in aortic SMCs and the atherogenice ApoE-/- mice by directly repressing the expression of the osteogenic protein IGF2. MiR-30e also reduces calcification in SMCs. Our data reveals miR-30e-Igf2 as a novel pathway in osteogenesis-mediated atherogenic progression. In addition to causing cardiovascular disease, altered lipoprotein metabolism has also been reported in patients with chronic kidney disease. Although the exact molecular mechanism is not clear, retention of lipid in the renal epithelial cells has been thought to promote epithelial cells to undergo epithelial-to-mesenchymal transition that causes fibrogenic responses in the kidney. The second part of this study investigates the role of LDL-c in the renal tubules in an animal model of Alport Syndrome. Alport Syndrome, characterized by hereditary progressive renal dysfunction, deafness and visual anomalies is an inherited chronic kidney disease that is caused by mutations in type IV collagen α chains. Our study in the COL4A3-/- “Alport mouse” reveals that Osteopontin (OPN), is highly expressed in the renal tubules of the Alport mouse and that it plays a major causative role in Alport pathology by regulation of Dynamin 3 (DNM3) and LDL receptor (LDLR) in the renal tubules of Alport mice. Our results suggest a new pathway for Alport pathology where tubular OPN causes DNM3-mediated enhanced cholesterol influx. Our data suggest that OPN may be a druggable therapeutic target for Alport Sydrome.
microRNA; cholesterol; Atherosclerosis; Alport Syndrome; SMCs; OPN
Ding, Wen, "Regulation of Cholesterol Homeostasis in Atherosclerosis and Alport Syndrome" (2017). Open Access Dissertations. 1904.
Available for download on Friday, July 06, 2018