Functional validation of the SMOC1 matrisomal protein network in Alzheimers disease

SMOC1 基质体蛋白网络在阿尔茨海默病中的功能验证

• 批准号: 10571158
• 负责人: David Edward Li-Kroeger
• 金额: $ 10.29万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571158
• 关键词: Acceleration; Adult; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-42; Amyloid beta-Protein; Architecture; Autopsy; Behavior; Biological Process; Biology; Brain; Calcium Binding; Cells; Central Nervous System; Clinical; Co-Immunoprecipitations; Cognition; Computer software; Data; Development; Development Plans; Disease; Disease Progression; Drosophila genus; Drosophila melanogaster; Drug Targeting; Environment; Ethics; Experimental Models; Extracellular Matrix; Extracellular Matrix Proteins; Functional disorder; Funding; Genetic; Goals; Grant; Histology; Homeostasis; Homologous Protein; Human; Immunoprecipitation; Individual; Institution; International; Investigation; Leadership; Link; Maintenance; Mass Spectrum Analysis; Mediating; Medicine; Mentors; Mentorship; Modeling; Nerve Degeneration; Neuroglia; Neurology; Neurons; Neurosciences; Pathogenesis; Pathologic; Pathology; Pathway Analysis; Pathway interactions; Proteins; Proteomics; Publishing; RNA Interference; Reporter; Research; Research Personnel; Research Training; Role; Scientist; Series; Signal Pathway; Signal Transduction; Structure; Systems Biology; Tauopathies; Technology; Therapeutic; Training; Transforming Growth Factor beta; Validation; WNT Signaling Pathway; Work; Writing; beta catenin; brain tissue; career; career development; cell type; clinically relevant; college; data integration; design; differential expression; drug development; experience; experimental study; fighting; fly; improved; in vivo; knock-down; laboratory experience; large scale data; link protein; meetings; member; mutant; neuronal cell body; neuropathology; neurophysiology; novel; novel marker; pre-clinical; programs; protein expression; protein function; protein protein interaction; skill acquisition; skills; symposium; tau Proteins; therapeutic target; trait; translational approach; translational potential; translational scientist

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.

项目摘要/摘要 该建议描述了五年的实验室培训经验，旨在导致独立 学术研究职业剖析了阿尔茨海默氏病的基本生物学（AD）。申请人的职业 目标是成为领导一项独立资助的研究提交的广告研究中的杰出科学家 团体。职业发展计划包括旨在扩大申请人科学技能的培训： （1）采用翻译方法来识别和表征与广告相关网络的关键蛋白 确定它们如何促进AD发病机理，（2）利用系统生物学方法剖析网络 当关键互连蛋白受到干扰时的行为，并且（3）使用跨物种方法识别 与特定的AD病理触发因素作为与AD斗争的治疗靶标相关的其他蛋白质。这 计划将领导力，精通授权和道德的额外培训纳入。期间 指导的研究培训，申请人将从事技能掌握，教学培训，半手， 国际会议，并与他的心理和心态委员会会面，然后过渡到 独立。拟议的研究旨在提高我们对生物学基础广告生物学的理解 通过研究AD相关蛋白网络的进展。我们已经确定了人类M42 与病理学密切相关的网络和AD认知的下降。基于网络分析， 与SPARC相关的模块化钙结合1（SMOC1）被确定为最好的网络驱动器 代表整个网络的行为。总体项目目标是验证和阐明 M42通过在果蝇模型中解剖SMOC1功能。我的跨物种方法将有力增强 我们对成人大脑中SMOC1的理解，该大脑预计将同时调节TGFβ和Wnt/β-catenin 信号通路，并确定在AD病理学中重要的其他M42蛋白质，从而告知治疗性 哺乳动物临床前广告模型的进一步研究的理由。这个五年项目将举行 在贝勒医学学院（Baylor Medicine），该机构拥有全国认可的遗传学研究计划， 神经科学和广告。神经病学系有培训早期的出色记录 研究人员成为成功翻译的研究人员。研究环境提供了最好的 智力环境，尖端技术和最先进的设施。该提案提供了广泛的 蛋白质组学数据的系统生物学分析，跨物种验证的研究经验 相关的蛋白质网络，以及其提出的驱动器蛋白SMOC1的功能表征，这是一种新颖的 AD中的生物标志物和潜在的治疗靶标。该建议及其相关培训计划的完成 将准备该申请人成为广告研究领域的独立科学家和领导者。