Date of Award

2018

Embargo Period

8-1-2024

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Regenerative Medicine and Cell Biology

College

College of Graduate Studies

First Advisor

Stephen Duncan

Second Advisor

Russell Norris

Third Advisor

Antonis Kourtidis

Fourth Advisor

Kyu-Ho Lee

Abstract

Hypercholesterolemia is a highly prevalent disease often treated with statin therapy. Statins lower serum cholesterol level by increasing the level of low-density lipoprotein receptors (LDLR) in liver cells, which bind to and remove low-density lipoprotein cholesterol (LDL-C). However, up to 39% of individuals fail to meet LDL-C goals. There are FDA approved alternatives to statins such as Evolocumab (PCSK9 inhibitor), as well as Mipromersen (oligonucleotide inhibitor of ApoB synthesis) and Lomitapide (MTTP inhibitor). Evolocumab is cost prohibitive and, along with statins, has little to no effect in patients with LDLR mutations such as Familial Hypercholesterolemia (FH), which is an inherited metabolic disease caused by decreased functionality of LDLRs. Additionally, Mipromersen and Lomitapide have FDA hepatotoxic warnings. Therefore, there is a need for new drug that lowers cholesterol levels independently from the LDLR pathway. In order to find an alternative compound with less toxicity, a small molecule screening was conducted using ELISA to measure changes in concentration of the major protein component of LDL-C, Apolipoprotein B, within the culture medium of iPSC-derived hepatocytes. We have access to nearly 120,000 novel molecules from the South Carolina Compound Collection (SC3) and tested a 10,000 compound chemically diverse subset of this library. Using human iPSC-derived hepatocytes, we aimed to identify novel compounds that reduce serum LDL-C level independent from the LDLR pathway. Through the course of the screening, we identified 11 compounds that reduced Apolipoprotein B levels, five of which are hypothesized to function through an LDLR-independent mechanism.

Rights

All rights reserved. Copyright is held by the author.

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