Deciphering innate immune signaling mechanisms in glial cells linking lifetime environmental exposures to neuroinflammation, protein aggregation and neurodegeneration in Parkinsons disease

点击翻译按钮获取中文摘要

Project Summary Parkinson’s disease (PD) is a debilitating movement disorder affecting the central nervous system (CNS) and is the second most common neurodegenerative disease worldwide after Alzheimer’s disease (AD). In addition to age and genetic background, environmental exposures are strongly associated with the development of PD. Agents implicated as risk factors for PD include pesticides and heavy metals, as well as infectious agents such as bacteria and viruses. The question of how cumulative environmental exposure to these agents throughout lifespan can promote the development of PD and related disorders remains largely unanswered. Inflammatory activation of glial cells in the brain is recognized as a critical early event in the prodromal phase of PD. Still, the molecular signals regulating conversion to this damaging inflammatory phenotype are only now being elucidated. This R35/RIVER application addresses the critical question of how the neuro-immune axis responds to environmental exposures encountered across the lifespan and how the combination of such exposures can trigger the onset of neurological disease through phenotypic conversion of glial cells to a neurotoxic state. To develop a deeper understanding of the molecular regulation of phenotypic changes in glial cells that underlie the progression from prodromal to symptomatic disease, the proposed studies will employ sophisticated transgenic models and molecular tools to address these scientific questions. The key scientific questions raised in this application coalesce around three well defined and interrelated goals: 1) Determine how developmental exposure to environmental neurotoxins modulates innate immune signaling in glial cells to alter the inflammatory response of the neuro-immune axis to subsequent toxic exposures during aging, 2) Identify key molecular pathways in glial cells altered by exposure to environmental neurotoxicants that regulate inflammatory responses of the brain to viral infection, and 3) Elucidate molecular signatures in regional populations of glial cells corresponding to various states of activation across the progression of neurological disease triggered by exposure to environmental neurotoxicants and viruses. The scientific goals addressed by this R35/RIVER application concerning multiple exposures across lifespan and risk for neurological disease will use both long-term studies involving exposure to multiple neurotoxic and infectious agents, as well as powerful approaches such as high-content imaging, neural network-based informatic analysis, single-cell and spatial transcriptomics and generation of new transgenic models. The R35 mechanism is ideal for integrating these complex resources and approaches with the personnel expertise necessary to address fundamental questions about how environmental exposures alter innate immune responses of the brain that promote the development of neurological disorders like PD and AD.