Date of Award

Spring 5-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmaceutical Sciences

First Advisor

Dr. Khaled Elsaid

Second Advisor

Dr. Ajay Sharma

Third Advisor

Dr. Miao Zhang

Fourth Advisor

Dr. Moom Roosan

Abstract

Gout is considered one of the most common forms of arthritis. It is characterized by sudden, severe attacks of pain, redness, and swelling in the joints. Management of acute gout attacks remains suboptimal, and hospitalizations due to poorly controlled flares have significantly increased over the past two decades. Colchicine is considered one of the first-line treatments for the relief of the symptoms associated with gout attacks. However, the use of colchicine for gout therapy has limitations due to the severe adverse effects, including fatalities. Acute gout is caused by deposition of monosodium urate (MSU) crystals in peripheral joints and surrounding tissues, which activate the resident macrophages to produce pro-inflammatory cytokines and consequently leads to an inflammatory response. The CD44 receptor is highly expressed in macrophages and plays an essential role in inflammation. The binding of endogenous ligands to CD44 on the surface of macrophages was shown to result in ligand internalization. In this project, we aimed to assess the role of CD44 using in vitro models of BMDMs of different genotypes and used Extra cellular domain shedding to study the impact on MSU phagocytosis, NF-kB translocation, NLRP3 inflammasome activation, and proinflammatory cytokine production in human macrophages. We also aimed to study the role of CD44 in regulating MSU-induced inflammation in a murine peritoneal model of acute gout. Moreover, we aimed to evaluate the feasibility of conjugating the P6 peptide, a 20-amino acid residue peptide that binds to CD44, to N-deacetylcolchicine via a hydrolyzable linker and study the efficacy and safety of the colchicine-P6 peptide conjugate in an in vitro model of MSU stimulated macrophages. our findings establish the CD44 receptor as a promising therapeutic target in gout, both through inhibition of NFkB pathway activation and modulation of macrophage phagocytosis of MSU crystals and in facilitating the uptake of small molecules that have an intracellular target in macrophages.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Available for download on Friday, May 13, 2022

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