Date of Award

Winter 2-27-2024

Embargo Period

3-13-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Drug Discovery and Biomedical Sciences

First Advisor

Yuri K. Peterson

Second Advisor

Alicia M. Braxton

Third Advisor

Stephen Tomlinson

Fourth Advisor

Danyelle Townsend

Fifth Advisor

Perry V. Halushka

Abstract

Osteoarthritis (OA) is a debilitating disease that affects 32.5 million US adults. It is characterized by loss of joint space and cartilage erosion, which eventually causes bone to rub on bone and causes pain and decreased mobility. Not only is it physically detrimental, but it is a financial burden as well. Current treatments of OA are used to control symptoms and leave intense side effects. Despite efforts in the past, there still is no disease-modifying OA drugs (DMOAD) approved on the market yet. The lack of disease-modifying drugs stems from poor understanding of the mechanisms initiating and driving the disease. As a result, there is a critical, medical need for improved agents for the treatment of OA. In response to this, our lab is identifying novel targets that could potentially be inhibited by small molecules to prevent the progression of OA. The results from our preliminary studies as well as prior research show that several complement factors are secreted in higher amounts in OA, especially complement C3. The complement cascade is important for innate immune responses against pathogens and can be activated through the classical, alternative, and mannose lectin pathway. All these pathways converge on the cleavage of complement component C3 and this is the central point of the cascade. This system is highly regulated and when this regulation breaks down, it could cause various diseases. In the case of OA, this overactive complement system could contribute to the degradation of the cartilage in the joint and the pathogenesis of OA. We also found that transcription factor signal transducer and activator of transcription 1 (STAT1) is involved in increasing C3 expression levels. STAT1 is involved in different inflammatory pathways specifically increasing IFN-γ expression and cancer. It has not been explored in the context of OA. This dissertation aims to identify the relationship between STAT1 and C3 in the context of OA, as well as using small molecule agents to target over expressed C3 expression to prevent progression of OA. First, we identified where STAT1 is associating with C3. Then, we discovered that STAT1 is involved in complement overexpression by using a specific STAT1 inhibitor, fludarabine. Lastly, we tested these inhibitors in vivo in Dunkin-Hartley guinea pigs to assess the inhibitor’s ability to attenuate cartilage damage in OA.

Rights

Copyright is held by the author. All rights reserved.

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