Epigenomic regulation of oxidative stress-producing innate immunity in neuroinflammation

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PROJECT SUMMARY / ABSTRACT Oxidative stress is a central part of innate immune-induced neurodegeneration in neurological disorders including multiple sclerosis (MS). However, the molecular mechanisms regulating oxidative stress gene circuits to promote neurotoxic immune responses remain poorly characterized. Emerging evidence supports a role for the epigenome in tightly regulating immune cell gene activity in MS. Yet, the epigenomic landscape and function in prooxidant, neurotoxic central nervous system (CNS) innate immune cells in MS remains unknown. Thus, discovery of drugs capable of selectively suppressing immune-driven neurodegeneration has been hindered by lack of molecular understanding of neurotoxic functions of CNS innate immune cells. The ultimate goal of this project is to define the regulatory landscape of prooxidant immune cells and identify mechanisms that translate epigenetic aberrations into innate-immune driven neurodegeneration for devising novel therapeutic interventions for MS. Our preliminary data discovered a molecular convergence of neurotoxic microglia and peripheral macrophages to a core oxidative stress gene signature in MS model. By applying an innovative experimental design with cutting-edge methods, this proposal aims to define the epigenetic and transcriptional components of oxidative stress-producing innate immune cells in a mouse model of neuroinflammation for MS through unbiased profiling of the open chromatin landscapes (Aim 1) and histone modifications (Aim 2). These molecular characterizations will identify key MS-related regulatory elements that will be functionally validated in vitro and in vivo with CRISPR interference assays (Aim 3). This project will provide a foundational epigenomic outlook on the molecular circuits governing prooxidant, neurotoxic immune responses in neuroinflammatory disease, and the research outcomes may reveal candidates for the development of new treatments for innate immune- mediated oxidative injury in MS and related conditions. The comprehensive training plan will enable the PI to achieve his career goal of launching a successful independent research laboratory dedicated to studying epigenomic mechanisms contributing to immune dysfunction in MS for targeted treatments. The MOSAIC UE5 mentoring, leadership, and diversity training will facilitate his transition to independence and enable the PI to enhance diversity in the biomedical workforce in the R00 phase and beyond. As a mentee in Dr. Katerina Akassoglou’s laboratory, a leader in neurovascular and immune mechanisms of MS pathogenesis, at the esteemed academic environment of Gladstone Institutes and University of California, San Francisco, the PI will obtain new training in functional epigenomics and CRISPR genome engineering during the K99 phase. The PI’s training and career development will be bolstered through an advisory committee of faculty with related expertise; and the PI’s participation in didactic activities such as coursework in epigenomics and seminars, will collectively allow the PI to complete this project and integrate these approaches for making meritorious contributions to the fields of MS and epigenomics in future independent research.