Summary (Overall) Our P20 application seeks to address unmet challenges of Parkinson’s disease (PD) by addressing the incredible complexity and heterogeneity in the disease etiology. We have assembled a consortium with multidisciplinary expertise and strong synergy that will perform collaborative and integrated research on PD pathogenic mechanisms. The result will lead to the preparation of a full-scale Udall Center grant application (P50). The overarching goal of our P20 and future P50 application is to determine the subtypes of PD associated with prodromal gut chronic inflammation, dissect the pathogenic mechanism underpinning gut-brain axis, and identify molecular biomarkers and novel therapeutics for subtypes of PD. Our overall hypotheses are that (1) chronic inflammation in the gastrointestinal system contributes to a subset of PD, and this is mediated by pathogenic interaction between LRRK2 and a-synuclein; (2) LRRK2 acts as an interface for the signaling pathways that leads to PD and IBD, and investigation of LRRK2 pathophysiology will help elucidate the molecular mechanisms for the gut-brain axis in the pathogenesis of PD. To test these hypotheses, we have proposed three highly synergistic projects. These projects are based on strong scientific premise and collection of promising data produced by all investigators. The strategic plan for our P20 application is to establish novel genetic LRRK2 disease models and a-synuclein transmission models to test gut-brain axis hypothesis for PD (Project 1 and 2), and to determine to what extent intestinal inflammation contributes to the development of PD and identify subtypes of PD based on the levels of genetic susceptibility to immune dysregulation (Project 3). Project 1. To decipher LRRK2 pathophysiology in mediating gut-brain axis of PD using novel genetic mouse models; Project 2. To elucidate the role of LRRK2 in the gastrointestinal manifestation of PD; Project 3. To understand the relationship of genetic, microbial, and intestinal inflammatory biomarkers in PD pathogenesis; our Admin Core is to provide central support to all activities of research, administration, finance, and communications among the three feasibility research projects and collaboration.