Date of Graduation
School of Medicine
Physiology, Pharmacology & Neuroscience
David P Siderovski
Rheumatoid arthritis (RA) is an autoimmune disease that is estimated to affect 1% of Americans. RA causes significant morbidity as a result of autoimmune stimuli inducing pro-inflammatory leukocyte recruitment to the joint. Despite the large effect on quality of life and significant research into RA pathophysiology, there is still much that is not known about the etiology of RA. Although effective treatment options do exist for RA, many of them carry significant risks of compliance-limiting adverse effects, high costs, and a subset of patients do not respond to treatment. This work attempts to respond to the limitations of current therapeutics by characterizing GPSM3 as a potential genetic marker and pharmaceutical target for RA through genetic and ex vivo modeling.;Based on data from compelling genome-wide association studies (GWAS), and supporting evidence from knockout mouse inflammatory arthritis models, we hypothesize that the G protein signaling modulator-3 (GPSM3) gene and protein play a significant role in the pathogenesis of RA. Current literature has identified two single-nucleotide polymorphisms (SNPs) in humans, rs204989 and rs204991, associated with protection from multiple autoimmune diseases including RA. We show that qRT-PCR analyses of whole blood-isolated RNA from volunteers homozygous for the GPSM3 SNPs show a decrease in GPSM3 transcript abundance compared to volunteers without the minor SNP alleles. Results from reporter gene studies support rs204989 as the causal SNP in decreasing GPSM3 promoter activity. In cell line models of neutrophil and monocyte physiology, GPSM3 deficiency results in disrupted migration patterns toward LTB4 and MCP-1, respectively. We hypothesize the minor allele of rs204989 represents a genetic factor contributing to the pathogenesis of RA, acting by decreasing GPSM3 expression and disrupting normal migration toward pro-inflammatory chemoattractants.
Gall, Bryan Jeffery, "From association to function: elucidating the role of G Protein Signaling Modulator 3 and variants in its gene locus in rheumatoid arthritis" (2016). Graduate Theses, Dissertations, and Problem Reports. 5640.