Contribution of the interaction between synuclein and tau in the pathophysiology of dementia with Lewy bodies

突触核蛋白和 tau 蛋白相互作用在路易体痴呆病理生理学中的贡献

• 批准号: 10221567
• 负责人: Lindsay Elizabeth Stoyka
• 金额: $ 4.66万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221567
• 关键词: Ablation; Alzheimer' s Disease; Alzheimer' s disease model; Area; Autophagosome; Axon; Axonal Transport; Behavioral; Binding; Binding Proteins; Biochemistry; Brain region; Cause of Death; Cell Death; Cessation of life; Clinic; Cognition; Cognition Disorders; Cognitive; Cognitive deficits; Competence; Corpus striatum structure; Data; Defect; Dementia; Dementia with Lewy Bodies; Development; Disease; Disease Progression; Doctor of Philosophy; Elderly; Endosomes; Environment; Exposure to; Foundations; Functional disorder; Generations; Genetic Variation; Goals; Human; Immunofluorescence Immunologic; Impaired cognition; Impairment; In Vitro; Injections; Kinetics; Knock-out; Knockout Mice; Laboratories; Lead; Lewy Bodies; Lewy body pathology; Lewy neurites; Lysosomes; Mentors; Microtubules; Modeling; Mus; Neurites; Neurobiology; Neurofibrillary Tangles; Neurons; Oral; Organelles; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Phase; Physicians; Play; Post-Translational Protein Processing; Prevalence; Recombinants; Research; Risk Factors; Role; Scientist; Signal Transduction; Solid; Structure; Substantia nigra structure; Techniques; Testing; Therapeutic; Training; Variant; Visuospatial; abeta oligomer; aging population; alpha synuclein; basal forebrain; base; behavior test; brain cell; calcein AM; career; cognitive function; cognitive performance; density; ethidium homodimer; experience; genome wide association study; in vivo; live cell imaging; mental state; monomer; mortality; neocortical; neuron loss; neuronal cell body; novel therapeutics; preservation; prevent; reduce symptoms; responsible research conduct; synuclein; synucleinopathy; tau Proteins; tau expression; tau interaction; translational approach

Project Summary This application is for F30 support of Lindsay Stoyka during the laboratory phase of her MD/PhD training. The scientific focus of the proposal is to examine how endogenous microtubule binding protein tau interacts with pathologic variants of alpha-synuclen to lead to cellular dysfunction and death, alpha-synuclein aggregation, and cognitive decline in Dementia with Lewy Bodies (DLB). DLB is the second most common cognitive disorder in the elderly and is characterized by fluctuating cognitive performance, visuospatial impairment, and frontosubcortical dysfunction. Intracellular aggregates of alpha-synuclein (termed Lewy bodies) are found in neurons throughout the deep cortical layers, paralimbic, and neocortical structures of DLB patients. The rationale behind the present proposal is that tau has been shown to bind to alpha-synuclein fibrils, but not monomer, suggesting a pathogenic interaction that is nonexistent in the non-diseased state. Additionally, Lewy body presence in the basal forebrain and limbic areas correlate with deteriorating cognitive function in humans. A clear synergistic effect of pathogenic alpha-synuclein and tau have been shown both in vitro and in vivo. However, few studies have explored the role of endogenous tau on alpha-synuclein aggregation in a DLB model. Determining the mechanisms at play in Lewy Body formation will facilitate the development of appropriate and specific therapies for DLB patients. The proposed training plan for Lindsay Stoyka is sponsored by her project mentors, Dr. David Standaert and Dr. Volpicelli-Daley. The overall goal of the training plan is to provide the PI with a solid foundation for a successful career as a physician scientist. A project based both in translational approaches, while focused on a disease-oriented pathogenesis, is the ideal training environment for any aspiring physician scientist. Included in the training plan are experiences that help the PI: 1) gain competence in a variety of techniques in neurobiology 2) collaborate with other scientists, 3) develop hypothesis-driven research, 4) present data in a written and oral format, 5) effectively integrate research with clinic, and 6) responsibly conduct research.

项目摘要 此应用程序用于林赛·斯托伊卡在医学博士/博士的实验室阶段的F30支持 训练。 该提案的科学重点是研究内源性微管结合蛋白tau如何 与α-突触蛋白的病理变体相互作用导致细胞功能障碍和死亡 路易体痴呆患者的聚集和认知能力下降(DLB)。DLB是第二种最常见的 老年人的认知障碍，以认知表现、视觉空间波动为特征 损害和额叶亚皮质功能障碍。α-突触核蛋白的胞内聚集体(称为刘易斯 小体)分布于深皮质、边缘旁和新皮质结构的神经元中。 病人。目前这项提议背后的理由是，tau已被证明与α-突触核蛋白结合 原纤维，但不是单体，这表明在非疾病状态下不存在致病相互作用。 此外，路易体在基底前脑和边缘区域的存在与认知能力的恶化有关。 在人类身上起作用。致病的α-突触核蛋白和tau的明显协同效应在 体外和体内。然而，很少有研究探讨内源性tau对α-突触核蛋白的作用。 DLB模型中的聚合。确定路易体形成中的作用机制将有助于 为DLB患者开发适当和特定的治疗方法。 为Lindsay Stoyka提出的培训计划由她的项目导师David博士赞助 斯坦德尔特和沃尔皮切利-戴利博士。培训计划的总体目标是为PI提供坚实的 为成为一名成功的内科科学家奠定了基础。这是一个基于翻译方法的项目， 虽然专注于面向疾病的发病机制，但对于任何有抱负的医生来说，都是理想的培训环境 科学家。 培训计划包括帮助PI获得各种能力的经验：1) 神经生物学技术2)与其他科学家合作，3)发展假说驱动的研究，4) 以书面和口头形式提供数据，5)有效地将研究与临床相结合，6)负责任地 开展研究。