Identifying signaling networks that contribute to Th17-mediated neuroinflammation

About This Grant

Project Summary Multiple Sclerosis (MS), a chronic autoimmune inflammatory disease of the Central Nervous System, affects approximately 2.3 million individuals globally, with nearly 1 million cases in the United States. It is more prevalent in females and typically manifests before the age of 30. Certain T helper 17 (Th17) cell populations are responsible for neuroinflammation and disease progression. However, patients with hyper-IgE syndrome and HIV infection are susceptible to infections due to the diminished Th17 cell count. Developing strategies to preserve Th17 cells while simultaneously blocking those that cause neuroinflammation and MS remains paramount. Transcriptional analyses have unveiled regulators of Th17 pathogenicity that facilitate immunomodulatory programs and promote pro-inflammatory programs. Nevertheless, mRNA measurements may not accurately correlate with protein abundance, and post-translational modifications such as phosphorylation play a crucial role in engaging signaling networks that drive autoimmunity, which are inadequately captured by mRNA-based approaches. To address this, we will develop a comprehensive suite of mass spectrometry proteomics tools to characterize protein abundance and phosphorylation in pathogenic Th17 cells at the systems level in the experimental autoimmune encephalomyelitis (EAE) model of MS. By comprehending the distinctive signaling pathways that distinguish pathogenic Th17 cells from other CD4 subtypes, we can identify potential targets for alleviating Th17-mediated autoimmune diseases while preserving non-pathogenic populations. Our preliminary proteomics and phosphoproteomics data has already identified novel drivers of pathogenic Th17 activity in the EAE model, which will be validated through small molecule inhibition and genetic approaches. In pharmacological studies, we will identify combinations of small molecule inhibitors that target multiple stages of pathogenic Th17s, offering superior protection against EAE disease compared to monotherapies. We will pursue mechanistic studies to elucidate the synergistic effects of targeting multiple pathways simultaneously in reducing EAE disease. The successful completion of this proposal will advance our fundamental understanding of autoimmune mechanisms mediated by Th17 cells and provide preclinical targets that could be utilized for future translational studies as therapeutic interventions for MS or other Th17-driven diseases.