Functional validation of the SMOC1 matrisomal protein network in Alzheimers disease

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 目标是通过领导一项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通过以下方式扩大申请者科学技能的培训： (1)使用翻译方法来识别和表征AD相关网络的关键蛋白质，以 确定它们在AD发病机制中的作用，(2)利用系统生物学方法剖析网络 当关键的相互连接的蛋白质受到干扰时的行为以及(3)使用跨物种的方法来识别 与特定AD病理触发相关的额外蛋白质，作为对抗AD的治疗靶点。这 PLAN包含了领导力、导师、拨款撰写和道德方面的额外培训。在……期间 指导研究培训，申请者将从事技能获取、教学培训、研讨会、 国际会议，以及与他的导师和指导委员会的会议，然后过渡到 独立。这项拟议的研究旨在提高我们对阿尔茨海默病的生物学基础的理解 通过研究AD相关蛋白网络的进展。我们已经确认了人类M42 网络与阿尔茨海默病的病理和认知功能下降密切相关。根据网络分析， SPARC相关的模块化钙结合-1(SMOC1)被认为是最好的潜在网络驱动因素 表示整个网络的行为。项目的总体目标是验证和阐明 M42在果蝇模型中的SMOC1功能。我的跨物种方法将有力地增强 我们对成人大脑中Smoc1的理解，它被预测为调节转化生长因子β和Wnt/β-连结蛋白 信号通路，并确定其他在AD病理中重要的M42蛋白，从而为治疗提供信息 哺乳动物临床前阿尔茨海默病模型进一步研究的理论基础。这个五年计划将主要进行 在贝勒医学院，这是一家拥有国家认可的遗传学研究项目的机构， 神经科学和AD。神经内科在早期培训方面有着出色的记录 研究人员成为成功的翻译研究人员。研究环境提供了最佳的 智力环境、尖端技术和最先进的设施。这项提议提供了一个广泛的 在蛋白质组数据的系统生物学分析、翻译的跨物种验证方面的研究经验 相关蛋白质网络及其新的驱动蛋白SMOC1的功能鉴定 阿尔茨海默病的生物标志物和潜在治疗靶点完成本建议书及其相关的培训计划 我将为这位申请者准备成为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 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.