权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanisms of Aggregated Alpha-Synuclein Induction and Progression

聚集的 α-突触核蛋白诱导和进展的机制

基本信息

批准号：
8799071
负责人：
BENOIT I GIASSON
金额：
$ 32.34万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8799071
关键词：
Accounting Affect Age-Years Aging Amyloid Autopsy Biological Brain Brain Stem Brain Tissue Transplantation Cerebrum Characteristics Cytoplasmic Inclusion Data Development Disease Disease Progression Embryo Future Genes Genetic Goals Health Homeostasis In Vitro Injection of therapeutic agent Intermediate Filaments Lead Lewy Bodies Lewy Body Dementia Mediating Missense Mutation Modeling Molecular Molecular Conformation Movement Disorders Mus Neuraxis Neurites Neurodegenerative Disorders Neuronal Dysfunction Neurons North America Parkinson Disease Pathology Patients Peripheral Peripheral Nerves Peripheral Nervous System Physiological Population Property Protein Conformation Proteins Proteome Quality of life Relative (related person)Reporting Research Project Grants Role Seminal Study models Testing Therapeutic Tissue Grafts Transgenic Mice age related alpha synuclein amyloid pathology conformer cross reactivity dopaminergic neuron early onset in vivo insight molecular mass mouse model mutant neurofilament neurotoxicity novel novel therapeutic intervention novel therapeutics prion-like protein misfolding tool transmission process

项目摘要

DESCRIPTION (provided by applicant): Parkinson disease (PD) is the most common movement disorder affecting over one million people in North America alone and results in an insidious reduction in the quality of life and ability to function. A hallmark of PD is the brain accumulation of neuronal cytoplasmic inclusions comprised of the protein alpha synuclein, but the presence of alpha synuclein brain aggregates is observed in a spectrum of neurodegenerative diseases, including dementia with Lewy body. Several findings suggest that alpha synuclein amyloid pathology may spread during disease progression by a self-templating alteration in protein conformation mechanism, however other alternative and/or synergistic biological mechanisms, as supported by our data, could also lead to progression of alpha synuclein pathology. From a therapeutic aspect it is critical to determine the relative importance, mechanisms and physiological consequences of the spread of alpha synuclein aggregation in disease. It this proposal, two major specific aims are proposed to inform on alpha synuclein induced and spread of disease: 1) Using both wild-type and disease causing mutant forms of alpha synuclein with unique aggregation properties, we will directly investigated that alpha synuclein aggregation can spread within the central nervous system and from the periphery with specific conformational characteristics. 2) We will assess the importance of alternative biological mechanisms including perturbation of the protein network homeostasis, neuronal intermediate filament integrity, neurotoxicity and age-related changes in the induction and propagation of alpha synuclein pathology by exogenous alpha synuclein challenges. These studies will provide critical insights on the mechanisms and the involvement of alpha synuclein aggregation in PD disease progression with the objective of guiding the development of novel therapeutics.

描述（由申请人提供）：帕金森病（PD）是最常见的运动障碍，仅在北美就影响超过100万人，并导致生活质量和功能能力的潜在降低。PD的标志是由蛋白质α突触核蛋白组成的神经元细胞质内含物的脑积累，但在一系列神经退行性疾病中观察到α突触核蛋白脑聚集体的存在，包括路易体痴呆。一些发现表明，α突触核蛋白淀粉样蛋白病理学可能在疾病进展期间通过蛋白质构象机制的自模板改变而传播，然而，如我们的数据所支持的，其他替代和/或协同生物学机制也可能导致α突触核蛋白病理学的进展。从治疗的角度来看，确定疾病中α突触核蛋白聚集的传播的相对重要性、机制和生理后果至关重要。在该提议中，提出了两个主要的具体目标来告知α突触核蛋白诱导和疾病传播：1）使用具有独特聚集性质的α突触核蛋白的野生型和致病突变形式，我们将直接研究α突触核蛋白聚集可以在中枢神经系统内传播，并且从具有特定构象特征的外周传播。2)我们将评估替代生物学机制的重要性，包括蛋白质网络稳态的扰动，神经元中间丝的完整性，神经毒性和年龄相关的变化，在诱导和传播的α突触核蛋白病理外源性α突触核蛋白的挑战。这些研究将提供关于α突触核蛋白聚集在PD疾病进展中的机制和参与的关键见解，目的是指导新疗法的开发。