Date of Completion

11-11-2014

Embargo Period

11-11-2017

Keywords

OPC, oligodendrocyte precursor cell, oligodendrocyte, differentiaiton, proliferation, screening, small molecule compounds

Major Advisor

Akiko Nishiyama

Associate Advisor

Joseph LoTurco

Associate Advisor

Randall Walikonis

Associate Advisor

Charlies Giardina

Associate Advisor

Dennis Wright

Field of Study

Physiology and Neurobiology

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Oligodendrocyte progenitor cells (OPCs) are precursor cells that give rise to oligodendrocytes, cells that form myelin, an arrangement of membrane sheaths enwrapping axons, necessary for fast transmission of electrical impulses in the nervous system. OPCs generate oligodendrocytes during development, adulthood and in pathological conditions.

Generation of oligodendrocytes from OPCs is in part regulated by growth factors. The major survival factor and mitogen for OPCs is platelet derived growth factor (PDGF). PDGF and its receptor, PDGF receptor A (PDGFRA), are critical regulators of OPC proliferation and their differentiation. PDGFRA gain-of-function can lead to excessive proliferation and is associated with a number of cancers, including glioma. In terms of the role of PDGFRA in OPC differentiation, there is evidence suggesting that signaling through PDGFRA needs to be inhibited in order for differentiation to occur.

The goal of this study is to identify small molecule compounds that inhibit Pdgfra transcription in oligodendrocyte precursor cells. We hypothesized that inhibition of Pdgfra transcription would result in inhibition of OPC proliferation and stimulation of their differentiation into mature oligodendrocytes. Identification of such compounds may provide a novel direction in drug design for demyelinating disorders or specific types of cancers caused by aberrant Pdgfra expression.

We identified a group of compounds that downregulated Pdgfra transcription in Oli-neu cells and that inhibited proliferation of Oli-neu cells and primary mouse OPCs but did not inhibit proliferation of primary mouse astrocytes, HEK 293 cells and glioblastoma-derived cell lines. These compounds did not however promote differentiation of primary OPCs.

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