Functional validation of the SMOC1 matrisomal protein network in Alzheimers disease

项目概要/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 我的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通过以下方式拓宽申请人科学技能的培训： (1)采用翻译方法来鉴定和表征AD相关网络的关键蛋白， 确定它们如何参与AD发病机制，（2）利用系统生物学方法剖析网络 行为时，关键互连蛋白质受到干扰和（3）使用跨物种的方法，以确定 与特定AD病理触发物相关的其他蛋白质作为对抗AD的治疗靶点。这 该计划还包括领导能力、指导、赠款发放和道德操守方面的额外培训。期内 指导研究培训，申请人将从事技能获取，教学培训，研讨会， 国际会议，并与他的导师和导师委员会会议，然后过渡到 独立这项拟议中的研究旨在提高我们对AD潜在生物学的理解 通过研究AD相关蛋白网络的进展。我们已经确认了人类的M42 网络与AD的病理和认知下降密切相关。根据网络分析， 钙离子相关的模块化钙结合-1（SMOC 1）被认为是一个潜在的网络驱动程序， 代表整个网络的行为。项目的总体目标是验证和阐明 M42通过在果蝇模型中剖析SMOC 1功能。我的跨物种方法将有力地增强 我们对成人大脑中SMOC 1的理解，预计它可以调节TGFβ和wnt/β-catenin 信号通路，并确定在AD病理学中重要的其他M42蛋白，从而为治疗提供信息。 进一步研究哺乳动物临床前AD模型的基本原理。这五年的计划，主要是 在贝勒医学院，一个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 成为成功的翻译研究者。研究环境提供了最好的 知识环境，尖端技术和最先进的设施。该提案提供了广泛的 在系统生物学分析蛋白质组数据，跨物种验证的实验室研究经验 相关蛋白质网络，沿着其提出的驱动蛋白SMOC 1的功能表征，一种新的 AD的生物标志物和潜在的治疗靶点。完成本建议书及其相关培训计划 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 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.