Investigating the Role of Inflammation and CD38 in SBMA Pathogenesis
Date of Award
2025
Degree Type
Thesis
Degree Name
Master of Science in Biomedical Sciences
First Advisor
Heather L. Montie, PhD
Second Advisor
Michelle Kanther, PhD
Third Advisor
Brian J. Balin, PhD
Abstract
Spinal and Bulbar Muscular Atrophy (SBMA) is a progressive neuromuscular disorder caused by a polyglutamine expansion in the androgen receptor, leading to lower motor neuron degeneration and muscle atrophy. Mitochondrial and metabolic dysfunctions contribute to disease, including depletion of NAD+ levels in skeletal muscle. Our lab identified overactive hydrolase activity of CD38 as a major contributor to the loss of NAD+. Since CD38 is an immune modulator and impaired mitochondrial function induces inflammation, we evaluated circulating plasma cytokines in a mouse model of SBMA (AR100Q). We found elevated levels of some pro- and anti-inflammatory cytokines and reduced levels of some pro- and anti-inflammatory cytokines. However, the inflammatory marker, CD45 protein, levels did not change in AR100Q quadriceps after forced exercise. In an effort to reduce inflammation and restore metabolic function, we treated AR100Q mice with prednisone, but it had no effect on CD45 expression, CD38 activity, or metabolic function. We also examined whether ubiquitous genetic deletion of CD38 could rescue motor function as observed with pharmacological inhibition of CD38. Surprisingly, CD38 knockout did not improve motor function of AR100Q mice. This suggests that complete loss of CD38 protein, including both its cyclase and hydrolase function, may complicate the benefit of mainly targeting the overactive hydrolase activity of CD38. Our findings suggest a complex role between immune and metabolic dysregulation in SBMA. Future studies will focus on different strategies to support immune and metabolic function in SBMA and specifically inhibiting the hydrolase activity of CD38 to improve metabolism and motor function in SBMA patients.
Recommended Citation
Hussain, Ali, "Investigating the Role of Inflammation and CD38 in SBMA Pathogenesis" (2025). PCOM Biomedical Studies Student Scholarship. 243.
https://digitalcommons.pcom.edu/biomed/243