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Influence of Aging on Pathogenic Alpha-Synuclein Strains and Transmission Mechanism

衰老对致病性α-突触核蛋白菌株的影响及传播机制

基本信息

批准号：
10199914
负责人：
Xiaobo Mao
金额：
$ 13.01万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10199914
关键词：
Acute Affect Affinity Age Aging Amyloid Proteins Atomic Force Microscopy Binding Binding Proteins Biochemical Biochemistry Biological Biophysics Brain Cerebrospinal Fluid Characteristics Chronic Classification Corpus striatum structure Cross-Sectional Studies Data Dementia with Lewy Bodies Diagnosis Digestion Disease Disease Progression Dopamine Electrophysiology (science)Endocytosis Endocytosis Pathway Endopeptidase K Evaluation Functional disorder Funding Gene Activation Growth Human In Vitro Injections Knock-out Knowledge Laboratory Research Lentivirus Lewy Bodies Lipid III Longitudinal Studies Lymphocyte Activation Mediating Methods Microscopy Molecular Structure Morphology Multiple System Atrophy Mus Nature Neurodegenerative Disorders Neurons Operative Surgical Procedures Parkinson Disease Parkinson&apos s Dementia Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Physiology Property Research Role Sampling Scanning Tunneling Microscopy Site Slice Structure Substantia nigra structure Synapses Synaptic Transmission Tauopathies Techniques Time Toxic effect Training Western Blotting age effect age related age related neurodegeneration alpha synuclein base brain tissue dopaminergic neuron experimental study gain of function in vivo indexing insight lens loss of function mechanical properties molecular imaging nano network dysfunction neuron loss neuronal circuitry nigrostriatal pathway novel strategies overexpression protein misfolding cyclic amplification receptor synucleinopathy tau Proteins transmission process two photon microscopy

项目摘要

“Influence of Aging on Pathogenic α-Synuclein Strains and Transmission Mechanism” Project Summary: Besides α-synuclein transmission mechanism, the role of distinct strains of α-synuclein is compelling to be understood. Understanding the influence of aging on the pathogenesis of synucleinopathies, including Parkinson's disease (PD), PD with dementia (PDD), dementia with Lewy body (DLB) and multiple system atrophy (MSA), is crucial for developing more effective symptomatic therapies. In this K01 proposal, three specific aims are proposed for understanding the influence of aging: (1) To generate and characterize pathogenic strain-specific α-syn from brain tissue/CSF of patients with PD/PDD/DLB/MSA to controls by the factor of aging longitudinally and cross-sectionally. (2) To understand the influence of age on distinct pathogenic α-syn strains from PD/PDD/DLB/MSA in vitro and in vivo. (3) To uncover the transmission mechanism of age-related distinct pathogenic α-synuclein. To achieve the 3 specific aims, 6 methods/steps are required: (i) Dr. Juan Troncoso and Dr. Liana Rosenthal will provide the training to candidate on handling human brain tissue/CSF. Drs. Ted and Valina Dawson, and Dr. Mark Mattson will train the candidate using the misfolded α-synuclein in brain tissue/cerebrospinal fluid (CSF) as templates, and with protein misfolding cyclic amplification (PMCA) technique, to generate distinct α-synuclein strains. (ii) Scanning tunneling microscopy (STM) will be applied for imaging molecular structures of distinct α-synuclein strains and distinguish the differences, and the alternative training will be available from Dr. Chen Wang if the potential problems appear. (iii) Atomic force microscopy (AFM) will be applied for observing assembly morphologies of distinct α-synuclein strains. Dr. Mingdong Dong will provide the training on studying nano-mechanical properties and dynamic growth features of distinct α-synuclein strains. (iv) Electrophysiology study on firing experiment will be hands- on training from Dr. Antonello Bonci. This training study is to understand the intrinsic and synaptic properties affected by distinct α-synuclein strains. (v) In vivo microscopy will be hands-on training from Dr. Da-Ting Lin. This training includes performing all necessary surgical procedure to insert gradient index (GRIN) lens into substantia nigra and two-photon microscopy. This study will allow candidate to study the dopamine neuronal circuit dysfunction affected by stereotaxically injected with distinct α-synuclein strains in striatum region for evaluation the transmission. (vi) Lymphocyte-activation gene 3 (LAG3) has been identified as α-synuclein preformed fibrils (PFF) receptor, so it is worth to explore whether LAG3 can mediate the transmission of distinct α-synuclein strains. Above all, this project proposed is to develop an independent research laboratory equipped to understand the distinct strains of amyloid proteins on misfolded structures, the transmission and the toxicity in neurodegenerative disorders, and to develop a programmatic line of research by successfully competing for funding.

“衰老对致病性α-突触核蛋白菌株的影响及传播机制”项目摘要：除了 α-突触核蛋白传输机制之外，不同菌株的 α-突触核蛋白的作用也引人注目明白了。了解衰老对突触核蛋白病发病机制的影响，包括帕金森病 (PD)、帕金森病伴痴呆 (PDD)、路易体痴呆 (DLB) 和多系统痴呆萎缩（MSA）对于开发更有效的对症疗法至关重要。在这个 K01 提案中，三个为了解衰老的影响提出了具体目标：（1）生成并表征来自 PD/PDD/DLB/MSA 患者脑组织/CSF 的致病菌株特异性 α-syn 与对照纵向和横向老化因子。 (2)了解年龄对不同性别的影响体外和体内 PD/PDD/DLB/MSA 致病性 α-syn 菌株。 (3) 揭开传动装置年龄相关的独特致病性α-突触核蛋白的机制。实现3个具体目标，6个方法/步骤需要： (i) Juan Troncoso 博士和 Liana Rosenthal 博士将为候选人提供处理培训人脑组织/CSF。博士。 Ted 和 Valina Dawson 以及 Mark Mattson 博士将使用以脑组织/脑脊液 (CSF) 中错误折叠的 α-突触核蛋白为模板，并以蛋白质错误折叠循环扩增（PMCA）技术，产生不同的α-突触核蛋白菌株。 (ii) 扫描隧道显微镜 (STM) 将用于对不同 α-突触核蛋白菌株的分子结构进行成像并区分如果出现潜在问题，王晨博士将提供替代培训。 (iii) 原子力显微镜（AFM）将用于观察不同α-突触核蛋白的组装形态菌株。董明东博士将提供纳米力学性能和动力学研究方面的培训不同 α-突触核蛋白菌株的生长特征。 (iv) 放电实验的电生理学研究将是手工的接受 Antonello Bonci 博士的培训。这项训练研究是为了了解内在和突触特性受不同 α-突触核蛋白菌株的影响。 (v) 体内显微镜技术将由林大廷博士进行实践培训。该培训包括执行所有必要的外科手术，将梯度折射率 (GRIN) 透镜插入黑质和双光子显微镜。这项研究将允许候选人研究多巴胺神经元在纹状体区域立体定向注射不同的 α-突触核蛋白菌株影响电路功能障碍评估传输。 (vi) 淋巴细胞激活基因 3 (LAG3) 已被鉴定为 α-突触核蛋白预成原纤维（PFF）受体，因此值得探讨LAG3是否可以介导不同的 α-突触核蛋白菌株。最重要的是，该项目提出的是建立一个独立的研究实验室能够了解淀粉样蛋白在错误折叠结构上的不同菌株、传输和神经退行性疾病的毒性，并成功开发了一系列研究争夺资金。