FUNCTIONAL VALIDATION OF A PLECTIN-ASSOCIATED ALZHEIMER'S DISEASE PROTEIN NETWORK

项目摘要/摘要 这份提案描述了一项为期五年的有指导的实验室培训经验，旨在导致独立的 研究阿尔茨海默病(AD)潜在生物学的学术研究生涯。申请人的职业生涯 目标是通过领导一个独立资助的研究，成为AD研究领域的知名科学家 一群人。职业发展计划包括旨在扩大申请者科学技能的培训， 包括：(1)利用系统生物学方法验证蛋白质网络和网络枢纽蛋白质 与AD关联；(2)使用跨物种分析来验证AD关联网络的组件 以及(3)应用翻译生物学的方法来确定这些 蛋白质网络有助于AD的发病机制和识别潜在的治疗靶点。这项计划包含了 在领导力、指导、拨款和道德方面的额外培训。在指导研究的一段时间内 培训，申请人将从事技能获取、教学培训、研讨会、国际会议、 与他的导师和导师委员会会面，随后过渡到独立。这个 拟议的研究旨在通过以下方式提高我们对阿尔茨海默病的基础和病理生理学的理解 研究与AD相关的蛋白质网络。我们已经确定了人类M4蛋白网络，即 与AD症状和神经病理学显著相关。根据网络分析，Plectin(Plec) 被标识为最能代表整个网络行为的潜在网络驱动程序。整个项目 目的是通过解剖果蝇模型中的PLEC功能来验证和阐明M4网络在果蝇模型中的作用。我的 跨物种的方法将有力地增强我们对PLEC和M4网络的了解，告知 哺乳动物临床前阿尔茨海默病模型进一步研究的治疗原理。这项为期五年的计划将在 主要在贝勒医学院(BCM)，这是一家在这两个领域都设有国家认可的系的机构 遗传学、神经科学和阿尔茨海默病研究，包括成熟的研究努力。美国商务部 神经病学在培训早期研究人员以获得高度成功方面有着出色的记录 翻译研究人员。研究环境提供了最好的智力环境和可用的 技术该提案在蛋白质组数据的系统生物学分析方面提供了广泛的研究经验， 翻译相关蛋白质网络的跨物种验证，以及一个基因的功能表征 提出网络驱动因素和AD治疗靶点。此外，拟议的职业发展计划将 让这位申请者成为AD研究领域的独立科学家和领导者。

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.