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: 9890542
• 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/9890542
• 关键词: Affect; Aging; Antibodies; Area; Award; Basic Science; Binding; Biochemical; Biochemistry; Biological Assay; Biological Markers; Biosensor; Blood; Blood Platelets; Blood specimen; Brain; C-terminal; Cell-Free System; Cells; Characteristics; Clinic; Clinical; Clinical Markers; 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; Plasma; Population; Positioning Attribute; Process; 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; disorder control; disorder risk; effective therapy; exosome; experience; genetic manipulation; imaging modality; insight; liquid biopsy; male; molecular imaging; novel; novel marker; outcome forecast; 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）之类的突触核苷病涉及异常 蛋白α-核蛋白的积累（α-Syn），尽管它已经近两个世纪了 首先描述，缺乏生物标志物极大地阻碍了疾病改良的发展 治疗和早期诊断。 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 蛋白质聚集体或“种子”也有证据表明α-syn在 诸如PD或MSA之类的疾病可能是这些疾病在其中看到的临床和病理差异的基础 突触核酸 异常的α-syn播种活性在患者的大脑提取物上与脑提取物不同 使用PD和MSA。 利用基于细胞的传感器的遗传操纵，（2）利用尖端分子和成像技术 在突触核苷病中的α-syn和PD（3）中降低α-Syn之间的差异 患者样品的血液成分中的播种活性可以像临床疾病进展的标记一样。 这项工作的含义包括促进PD和MSA患者的诊断和疗法。 申请人是肯塔基大学神经病学系的助理教授，他坚定地 作为独立翻译科学家的学术职业是神经退行性的 疾病。 出色的临床文档和记录系统，以及受这些影响的非常非常非常a的人口 疾病并在VA的诊所紧随其后 提案将在经验丰富的导师团队的指导下进行 主要导师，在运动者的临床研究方面拥有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。 导师。他们是血小板的血小板专家 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。 研究运动障碍患者外围物中综合蛋白质的技术。 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。 可以通过利用的生物标志物检测和区分触突变。 α-Syn播种活动的差异。 对PD和相关神经退行性研究的新生物标志物研究的独立研究。