Functional validation of the SMOC1 matrisomal protein network in Alzheimers disease

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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 filed by leading an independently funded research group. The career development plan includes training designed to broaden the applicant’s scientific skillset by: (1) employing translational approaches to identify and characterize key proteins of an AD-associated network to determine how they contribute to AD pathogenesis, (2) utilizing systems biology approaches to dissect network behavior when key interconnected proteins are perturbed and (3) using cross-species approaches to identify additional proteins linked to specific AD pathological triggers as therapeutic targets in the fight against AD. This plan incorporates additional training in leadership, mentorship, grant-writing, and ethics. During the period of mentored research training, the applicant will engage in skills acquisition, didactic training, seminars, international conferences, and meetings with his mentor and mentorship committee, followed by a transition to independence. The proposed research aims to improve our understanding of the biology underlying AD progression through investigation of an AD-associated protein network. We have identified the human M42 network that is strongly correlated with pathology and declining cognition in AD. Based on network analyses, SPARC Related Modular Calcium Binding-1 (SMOC1) 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 M42 by dissecting SMOC1 function in the Drosophila model. My cross-species approach will powerfully enhance our understanding of SMOC1 in the adult brain, which is predicted to modulate both TGFβ and wnt/β-catenin signaling pathways, and identify additional M42 proteins important in AD pathology, thus 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, an institution with nationally recognized research programs in genetics, neuroscience and AD. The Department of Neurology has an outstanding track record of training early stage investigators to become successful translational researchers. The research environment provides the best intellectual environment, cutting edge technologies and state-of-the art facilities. The proposal provides a broad research experience in systems biology analysis of proteomic data, cross-species validation of a translationally relevant protein network, along with functional characterization of its proposed driver protein SMOC1, a novel biomarker and potential therapeutic target in AD. Completion of this proposal and its associated training plan will prepare this applicant to become an independent scientist and leader in the AD research field.