Project Summary/Abstract This proposal describes a five-year mentored laboratory training experience designed to lead to an independent academic research career dissecting the underlying biology of Alzheimer’s disease (AD). The applicant’s career goal is to become a prominent scientist in the AD research field by leading an independently-funded research group. The career development plan includes training designed to broaden the applicant’s scientific skillset, including: (1) utilizing systems biology approaches to validate protein networks and network hub proteins associated with AD, (2) employing cross-species analyses to validate components of an AD-associated network and dissect its underlying biology, and (3) applying translation biology approaches to determine how these protein networks contribute to AD pathogenesis and identify potential therapeutic targets. This plan incorporates additional training in leadership, mentorship, grant-writing, and ethics. During a period of mentored research training, the applicant will engage in skills acquisition, didactic training, seminars, international conferences, meetings with his mentor and mentorship committee, followed by a transition to independence. The proposed research seeks to improve our understanding of the underpinnings and pathophysiology of AD by investigating an AD-associated protein network. We have identified the human M4 protein network that is significantly associated with AD symptoms and neuropathology. Based on network analyses, Plectin (Plec) was identified as a potential network driver that best represents the behavior of the entire network. The overall project goal is to validate and elucidate the role of M4 network by dissecting Plec function in the Drosophila model. My cross-species approach will powerfully enhance our understanding of Plec and the M4 network, informing a therapeutic rationale for further studies in mammalian preclinical AD models. This five-year project will take place primarily at Baylor College of Medicine (BCM), an institution with nationally recognized departments in both genetics, neuroscience, and AD research, including well-established research efforts. The Department of Neurology has an outstanding track record of training early stage investigators to become highly successful translational researchers. The research environment provides the best intellectual environment and available technology. The proposal provides a broad research experience in systems biology analysis of proteomic data, cross-species validation of a translationally relevant protein network, and functional characterization of a proposed network driver and AD therapeutic target. In addition, the proposed career development plan will prepare this applicant to become an independent scientist and leader in the AD research field.