Enhancing diagnosis of Parkinson's disease and multiple system atrophy via detection of alpha-synuclein seeding activity

通过检测 α-突触核蛋白播种活性增强帕金森病和多系统萎缩的诊断

• 批准号: 10454097
• 负责人: Tritia Yamasaki
• 金额: --
• 依托单位: VA MEDICAL CENTER - LEXINGTON, KY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454097
• 关键词: Affect; Aging; Antibodies; Area; Award; Basic Science; Binding; Biochemical; Biochemistry; Biological Assay; Biological Markers; Biosensor; Blood; Blood Platelets; Blood specimen; Braak' s hypothesis; Brain; C-terminal; Cell-Free System; Cells; Characteristics; Clinic; Clinical; Clinical Research; Consent; DNA Sequence Alteration; Deep Brain Stimulation; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Documentation; Early Diagnosis; Elderly; Engineering; Epitopes; Erythrocytes; Evaluation; Expenditure; Exposure to; FDA approved; Faculty; Fluorescence Resonance Energy Transfer; Gender; Genetic; Goals; Healthcare; Imaging Techniques; In Vitro; Investigative Techniques; Kentucky; Knowledge; Lead; Ligands; Liquid substance; Mentors; Methods; Modality; Molecular; Molecular Conformation; Motor; Movement; Movement Disorders; Multiple System Atrophy; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurology; Parkinson Disease; Pathogenicity; Pathologic; Pathology; Patients; Peripheral; Persons; Plasma; Population; Positioning Attribute; Process; Prognosis; Property; Proteins; Publishing; Records; Research; Sampling; Seeds; Solubility; Structure; System; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Toxin; Training; Training Programs; Universities; Veterans; Whole Blood; Work; accurate diagnosis; alpha synuclein; amplification detection; base; career; cerebral atrophy; collaborative environment; detection method; disorder control; disorder risk; effective therapy; exosome; experience; genetic manipulation; imaging modality; insight; liquid biopsy; male; molecular imaging; novel; novel marker; patient population; prion-like; professor; prognostic; protein aggregation; rare condition; sensor; success; synuclein; synucleinopathy; translational scientist; transmission process

Synucleinopathies such as Parkinson's disease (PD) and multiple systems atrophy (MSA) involve abnormal accumulation of the protein alpha-synuclein (α-syn). Although it has been nearly two centuries since PD was first described, a dearth of biomarkers has greatly impeded progress toward development of disease-modifying treatments and accurate and early diagnosis. This proposal is based on the hypothesis that pathology in these diseases propagates through the brain via a mechanism in which transcellular movement of misfolded α-syn protein aggregates or “seeds” occurs. There is also evidence that pathogenic α-syn has diverse structures in diseases such as PD or MSA, that may underlie the clinical and pathologic differences seen in these synucleinopathies. This proposal utilizes a novel cell-based assay that has been shown to detect and quantify abnormal α-syn seeding activity that differs both biochemically and structurally in brain extracts from patients with PD and MSA. In this project we propose to (1) optimize the ability to detect aggregated forms of α-syn utilizing genetic manipulation of a cell-based sensor, (2) utilize cutting edge molecular and imaging techniques to parse out differences between α-syn in the synucleinopathies MSA and PD, and (3) determine whether α-syn seeding activity in blood components of patient samples can serve as a marker for clinical disease progression. The implications of this work include facilitation of diagnosis and therapeutics for patients with PD and MSA. The applicant is an Assistant Professor in the Department of Neurology at University of Kentucky, who is firmly committed to an academic career as an independent translational scientist in the area of neurodegenerative disease. The proposed training will take advantage of the rich and collaborative environment at the VA, the excellent clinical documentation and records system, and the very relevant patient population affected by these diseases and followed in clinic at the VA: all are factors that are integral and crucial to the success of this proposal. Training will be conducted under the direction of an experienced mentor team. Dr. John Slevin, will be the primary mentor, and has over 40 years of expertise in clinical research in Movement Disorders and holds a Merit Award at the VA in basic science research. Dr. Sidney Whiteheart and Dr. Haining Zhu will serve as co- mentors. They are experts in platelet biochemistry and abnormal protein aggregation, respectively, hold Merit Awards in their fields, and are also faculty in the Department of Molecular and Cellular Biochemistry at University of Kentucky. These mentors have been specially selected to advance the candidate’s knowledge of molecular techniques for investigating aggregated proteins in peripheral fluids of patients with movement disorders. Training during this proposal includes advanced genetic, molecular, and imaging-based techniques for protein amplification and detection, and techniques for isolation and analysis of exosomal and platelet fractions from whole blood. These components will be essential to completing the applicant’s immediate goal of developing a biomarker that can detect and differentiate between synucleinopathies in peripheral samples by utilizing differences in α-syn seeding activity. The comprehensive training program will position the applicant to conduct independent research in the study of novel biomarkers in PD and related neurodegenerative disease.

诸如帕金森氏病（PD）和多个系统萎缩（MSA）之类的突触核酸疾病涉及异常 蛋白质α-突触核蛋白（α-Syn）的积累。尽管PD为几乎是两个世纪 首先描述的是，生物标志物的死亡极大地阻碍了疾病改良的发展 治疗以及准确和早期诊断。该提议基于以下假设 疾病通过一种机制传播大脑的机制，在这种机制中，跨折叠α-Syn的跨细胞运动 发生蛋白质聚集体或“种子”。也有证据表明，致病性α-Syn具有多种结构 PD或MSA等疾病可能是这些疾病的基础 综合病。该提案利用一种新型基于细胞的测定法，该测定已显示出来检测和量化 异常的α-syn播种活性在患者的脑提取物中在生化和结构上不同 与PD和MSA。在这个项目中，我们建议（1）优化检测α-Syn的汇总形式的能力 使用基于细胞的传感器的基因操纵，（2）利用尖端分子和成像技术 解析突触核苷病和PD中α-Syn之间的差异，（3）确定α-syn是否是否 患者样品的血液成分中的播种活性可以作为临床疾病进展的标志物。 这项工作的含义包括促进PD和MSA患者的诊断和治疗。 申请人是肯塔基大学神经病学系的助理教授，他首先是 致力于神经退行性领域的独立翻译科学家的学术生涯 疾病。拟议的培训将利用弗吉尼亚州的富人和协作环境 出色的临床文档和记录系统，以及受这些影响的非常相关的患者群体 疾病并遵循VA的诊所：所有因素都是对此不可或缺的因素 提议。培训将在经验丰富的心理团队的指导下进行。约翰·斯莱文（John Slevin）博士将是 主要导师，在运动障碍临床研究方面拥有40多年的专业知识，并拥有 弗吉尼亚州基础科学研究的优点奖。 Sidney Whiteheart博士和Haining Zhu博士将担任 导师。他们分别是血小板生物化学和异常蛋白质聚集的专家 他们的领域奖项，也是大学分子和细胞生物化学系的教师 肯塔基州。这些导师已被专门选择以促进候选人的分子知识 研究运动障碍患者外周流体中综合蛋白的技术。 该建议期间的培训包括蛋白质的高级遗传，分子和基于成像的技术 放大和检测以及用于隔离和分析外泌体和血小板分数的技术 全血。这些组成部分对于完成申请人的直接目标至关重要 可以通过使用的生物标志物，可以通过使用外周种样品中的突触核苷病和区分的生物标志物 α-syn播种活性的差异。综合培训计划将定位申请人进行 对PD和相关神经退行性疾病的新生物标志物研究的独立研究。