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

项目总结/摘要 该提案描述了为期五年的指导实验室培训经验，旨在培养独立的 学术研究生涯解剖阿尔茨海默病（AD）的潜在生物学。申请人的职业 目标是通过领导一项独立资助的研究，成为AD研究领域的杰出科学家 组职业发展计划包括旨在扩大申请人科学技能的培训， 包括：（1）利用系统生物学方法验证蛋白质网络和网络中心蛋白质 与AD相关，（2）采用跨物种分析来验证AD相关网络的组件 并剖析其潜在的生物学，（3）应用翻译生物学方法，以确定如何这些 蛋白质网络有助于AD发病机制并确定潜在的治疗靶点。该计划包括 在领导力、指导、赠款撰写和道德操守方面的额外培训。在一段指导研究期间， 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举行会议，然后过渡到独立。的 拟议的研究旨在通过以下方式提高我们对AD基础和病理生理学的理解 研究AD相关蛋白质网络我们已经确定了人类M4蛋白网络， 与AD症状和神经病理学显著相关。基于网络分析， 被识别为最能代表整个网络行为的潜在网络驱动程序。整个项目 目的是通过在果蝇模型中剖析Plec功能来验证和阐明M4网络的作用。我 跨物种的方法将有力地增强我们对Plec和M4网络的理解， 在哺乳动物临床前AD模型中进一步研究的治疗原理。这个为期五年的项目将在 主要是在贝勒医学院（Baylor College of Medicine，简称BLM），这是一所在两个领域都拥有国家认可的部门的机构。 遗传学、神经科学和AD研究，包括成熟的研究工作。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 翻译研究者研究环境提供了最好的智力环境， 技术.该提案为蛋白质组数据的系统生物学分析提供了广泛的研究经验， 跨物种验证的相关蛋白质网络，和功能表征的 提出了网络驱动程序和AD治疗靶点。此外，拟议的职业发展计划将 使申请人成为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.