Elucidating the role of ARID5A in central nervous system inflammation

/Abstract Microglia are the resident immune cells of the central nervous system (CNS), playing essential roles in both tissue maintenance and injury response. In diseases like multiple sclerosis (MS), persistent microglial activation drives neuroinflammation, axonal injury, and neurodegeneration. Yet, the molecular mechanisms that maintain chronic microglial activation remain poorly defined, and no approved therapies directly target this compartment of disease. Although transcriptomic profiling has traditionally guided our understanding of inflammation, these approaches provide limited resolution over the rapid and reversible gene expression changes required for immune homeostasis. Post-transcriptional mechanisms, particularly those mediated by RNA-binding proteins (RBPs), enable more nuanced control of RNA fate. RBPs are emerging therapeutic targets in neurological disease in neurons, however, their function in microglial inflammation is largely unexplored. This proposal focuses on ARID5A, an RBP I have found to be upregulated in lesion-associated microglia in MS and experimental autoimmune encephalomyelitis (EAE), a model for MS. Preliminary studies show that ARID5A is required for sustained expression of interferon-stimulated genes in microglia, suggesting a central role in maintaining chronic CNS inflammation. This project will test the hypothesis that ARID5A enables microglia to sustain inflammatory gene expression by regulating RNA at multiple post-transcriptional checkpoints. I will define the cell autonomous role of ARID5A in microglial activation during CNS autoimmunity (Aim 1), and how ARID5A controls protein output in inflammatory microglia using ribosome profiling (Ribo-seq) and RNA-seq in both primary mouse and human iPSC-derived microglia (Aim 2). By uniting transcriptomic, translational, and regulatory profiling across complementary in vivo mouse and in vitro human systems, this work will define how dysregulated post-transcriptional control disrupts immune balance in microglia and contributes to chronic CNS inflammation. The complementary expertise of the Yeo lab in RNA biology and the Mendiola lab in neuroinflammation provides an ideal environment to execute this research plan and prepare me for a career as a physician-scientist in neuroimmunology and functional genomics. Project Number: 1F31NS149734-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Grace McAuley | Institution: UNIVERSITY OF CALIFORNIA, SAN DIEGO, LA JOLLA, CA | Award Amount: $43,565 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F03A-V (21)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11390178