Role of Rab10 in Alzheimer's disease

Rab10 在阿尔茨海默病中的作用

基本信息

批准号：
10589040
负责人：
Zhiyong Liu
金额：
$ 11.09万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-15 至 2023-12-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10589040
关键词：
3&apos Untranslated Regions Academia Acceleration Acute Advisory Committees Alleles Alzheimer&apos s Disease Animal Model Atrophic Attenuated Automobile Driving Biochemistry Biology Biophysics Brain Brain Diseases Cells Cellular biology Complement Coupled Data Disease Disease Progression Disease model Disease susceptibility Flow Cytometry Foundations Functional disorder Future GTP Binding GTPase-Activating Proteins Genetic Genetic Variation Goals Grant Guanine Nucleotide Exchange Factors Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Immune response Immunologics In Vitro Inflammasome Inflammation Inflammatory Inflammatory Response Investigation Label Laboratory Research Link Liquid substance Mass Spectrum Analysis Mediating Membrane Mentors Mentorship Messenger RNA Microglia Molecular Mus Nerve Degeneration Neurodegenerative Disorders Odds Ratio Oligonucleotides Pathology Pathway interactions Patients Phagocytes Phase Phenotype Postdoctoral Fellow Predisposition Process Publishing Research Role Scanning Series Single Nucleotide Polymorphism Techniques Testing Therapeutic Training Universities Work Writing apolipoprotein E-4 candidate validation career comparison control cytokine disease phenotype experience experimental study in vivo innate immune function interest knock-down mouse model neuroinflammation neuron loss neuropathology novel protein aggregation rab GTP-Binding Proteins recruit resilience response skills tau Proteins tau aggregation trafficking transcriptomics uptake

3&apos Untranslated Regions Academia Acceleration Acute Advisory Committees Alleles Alzheimer&apos s Disease Animal Model Atrophic Attenuated Automobile Driving Biochemistry Biology Biophysics Brain Brain Diseases Cells Cellular biology Complement Coupled Data Disease Disease Progression Disease model Disease susceptibility Flow Cytometry Foundations Functional disorder Future GTP Binding GTPase-Activating Proteins Genetic Genetic Variation Goals Grant Guanine Nucleotide Exchange Factors Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Immune response Immunologics In Vitro Inflammasome Inflammation Inflammatory Inflammatory Response Investigation Label Laboratory Research Link Liquid substance Mass Spectrum Analysis Mediating Membrane Mentors Mentorship Messenger RNA Microglia Molecular Mus Nerve Degeneration Neurodegenerative Disorders Odds Ratio Oligonucleotides Pathology Pathway interactions Patients Phagocytes Phase Phenotype Postdoctoral Fellow Predisposition Process Publishing Research Role Scanning Series Single Nucleotide Polymorphism Techniques Testing Therapeutic Training Universities Work Writing apolipoprotein E-4 candidate validation career comparison control cytokine disease phenotype experience experimental study in vivo innate immune function interest knock-down mouse model neuroinflammation neuron loss neuropathology novel protein aggregation rab GTP-Binding Proteins recruit resilience response skills tau Proteins tau aggregation trafficking transcriptomics uptake

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项目摘要

1 Project Summary: “Role of Rab10 in Alzheimer’s disease, K99/R00” 2 Candidate: My long-term career goals center on the establishment of a leading research laboratory in 3 academia focused on defining key molecular mechanisms underlying neurodegeneration and Alzheimer’s 4 disease (AD). Specifically, my recent research interests have narrowed to ask how key regulators of endocytic 5 trafficking pathways, particularly Rab GTPases and their modifiers, contribute to neuroinflammation associated 6 with AD. I am a biochemist with training in biophysics and cell biology, with the included proposal for additional 7 training in mouse models of disease. These training experiences will facilitate future investigations in molecular 8 mechanisms underlying endocytic dysfunction that manifest in disease relevant phenotypes. 9 Training: Here I propose a series of training that include a translational in vivo experiment in mouse models 10 coupled with formal coursework to accelerate my trajectory towards independence in the R00 phase. These 11 training experiences will be facilitated through mentorship from Dr. Andrew West, in addition to a Transition 12 Advisory committee at Duke University composed of Dr. Patrick Sullivan, an expert in mouse AD models, Dr. 13 Carol Colton, an expert in microglia function in AD models, and Dr. Robert Lefkowitz, a Nobel-laureate expert 14 in biochemistry and cell biology. Formal course work that is planned will further enhance training on in vivo 15 study approaches, grant writing, mentoring skills, lab management and responsible conduct in research. 16 Research: Recently, a single nucleotide polymorphism in the Rab10 3’UTR rs142787485 has been linked with 17 strong resiliency to AD susceptibility. Transcriptomic analysis reveals Rab10 mRNA as higher in AD patient 18 brains compared to healthy controls. My latest post-doctoral work disclosed that the Rab10 GTPase, highly 19 expressed in phagocytic cells, operates in a specific compartment of the endolysosomal pathway to control 20 fluid phase macropinocytosis. Preliminary data included herein suggests knockdown of Rab10 decreases the 21 internalization of aggregated tau in mouse primary microglia. Recent findings suggest internalized tau 22 aggregates break endolysosomes in microglia that stimulate inflammasome activation and the secretion of 23 damaging cytokines. Inflammasome activation may accelerate tau pathology, potentially linking Rab10 with 24 neuroinflammatory pathways important in AD. I plan to explore this novel disease-associated cycle in K99 and 25 R00 work. In the K99 phase, I would test the hypothesis that suppression of Rab10 in the P301S Tau/APOE4 26 mouse model ameliorates neuroinflammation and neuropathology. In the R00 phase, I plan to investigate how 27 Rab10 might regulate aggregated tau uptake, processing, and responses in microglia, as well as key 28 regulators of Rab10 activity that influence different endocytic trafficking pathways and immunological 29 responses. These proposed experiments would start to elucidate the potential roles of Rab10 in AD, and 30 identify novel pathways that might be exploited in the future for therapeutic gain. 31 32 33

1项目摘要：“ Rab10在阿尔茨海默氏病中的作用，K99/R00” 2候选人：我的长期职业目标中心建立了领先的研究实验室 3学术界的重点是定义神经退行性基础的关键分子机制和阿尔茨海默氏症 4疾病（AD）。具体而言，我最近的研究兴趣已缩小以询问内吞的关键调节因子 5个贩运途径，尤其是RAB GTPases及其修饰符，有助于与神经炎症有关 6与广告。我是一名生物化学和细胞生物学培训的生物化学家，其中包括额外的建议 7疾病小鼠模型的培训。这些培训经验将促进未来的分子研究在相关表型中表现出的8种机制。 9培训：我在这里提出了一系列培训，其中包括鼠标模型中的体内翻译实验 10结合正式的课程，以加速我在R00阶段独立的轨迹。这些除了过渡外，还将通过安德鲁·韦斯特（Andrew West）博士的心态来准备11种培训经验 12杜克大学的咨询委员会由鼠标广告模型专家帕特里克·沙利文（Patrick Sullivan）博士组成。 13 Carol Colton，AD模型中的小胶质细胞功能专家，Robert Lefkowitz博士（诺贝尔语言专家） 14生物化学和细胞生物学。计划的正式课程工作将进一步增强体内培训 15研究方法，赠款写作，心理技能，实验室管理和负责任的研究。 16研究：最近，RAB10 3'UTR RS142787485中的单个核苷酸多态性与 17对AD敏感性的强弹性。转录组分析揭示了AD患者的RAB10 mRNA较高与健康对照相比，有18个大脑。我最新的博士后工作揭示了Rab10 GTPase，高度 19在吞噬细胞中表达的19个在内溶解体途径的特定隔室中运行 20液相大细胞增多症。本文包含的初步数据表明，敲低Rab10降低了 21小鼠原代小胶质细胞中聚集的tau的内在化。最近的发现表明内部化tau 22个骨料中断的小胶质细胞中的内溶性，可刺激炎症体激活和分泌 23破坏性细胞因子。炎性体激活可能会加速tau病理学，可能将RAB10与 24神经炎症途径在AD中很重要。我计划在K99和 25 R00工作。在K99阶段，我将检验以下假设：p301s tau/apoe4中的rab10抑制 26小鼠模型可以改善神经炎症和神经病理学。在R00阶段，我计划调查如何 27 RAB10可能会调节小胶质细胞中的总tau摄取，加工和反应以及钥匙 28 RAB10活性的调节剂，影响不同的内吞交易途径和免疫学 29个回应。这些提出的实验将开始阐明Rab10在AD中的潜在作用，并且 30确定将来可能会探索的新型途径，以获得治疗性增长。 31 32 33