A Large-scale Extracellular Vesicle RNA-seq Resource for Parkinsons Disease

帕金森病的大规模细胞外囊泡 RNA-seq 资源

• 批准号: 10706937
• 负责人: Xianjun Dong
• 金额: $ 225万
• 依托单位: TRANSLATIONAL GENOMICS RESEARCH INST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706937
• 关键词: Acceleration; Affect; Age; Biological Assay; Brain; Brain Diseases; CD81 gene; Cells; Circulation; Clinical Trials Design; Collection; Communities; DNA Transposable Elements; Data; Data Analyses; Data Set; Deposition; Detection; Development; Disease; Disease Progression; Evaluation; Exons; Functional disorder; Future; Genes; Genetic Transcription; Growth Associated Protein 43; Immunoassay; Knowledge Portal; Label; Longitudinal Studies; Measures; Medical; Messenger RNA; Methodology; Monitor; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Oligodendroglia; Organ; Parkinson Disease; Participant; Pathway interactions; Patients; Peripheral; Persons; Phenotype; Plasma; Population; Process; Publications; Quality Control; RNA; RNA Splicing; RNA metabolism; Research; Research Personnel; Resources; Role; Sampling; Scientific Inquiry; Therapeutic; Time; Translating; Work; Writing; alpha synuclein; biomarker discovery; biomarker validation; biotypes; brain cell; candidate marker; cell type; circular RNA; cohort; data submission; diagnostic accuracy; disorder control; extracellular; extracellular vesicles; improved; innovation; nervous system disorder; non-motor symptom; novel strategies; patient stratification; prevent; sample collection; therapeutic development; therapeutic target; tool; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT Parkinson's disease (PD) is a devastating and progressive neurological disease that impacts 6 million people worldwide. The lack of validated biomarkers of PD has hampered improvements in predicting disease progression, identifying new pathways for therapeutic development, and patient stratification toward rational clinical trial design. Recent advancements in the capture and characterization of extracellular, circulating RNAs (exRNAs) have spurred the identification of disease mechanisms, therapeutic target engagement, and biomarker discovery in neurological diseases. Extracellular vesicles (EVs), which can take pieces of cellular cargo and make their way into circulation, offer a unique opportunity to monitor RNA changes in patients living with PD. Our team has helped to mature the capture and characterization of EVs towards deployment for monitoring disease – using strategies that can look at the cargo from the total EV population as well as EVs derived from specific brain cell types affected by diseases like PD. The longitudinal collection of thousands of samples, with extensive phenotyping from hundreds of patients in the AMP-PD cohorts, offers an unprecedented opportunity to develop a comprehensive resource, that can easily be accessed and utilized by the PD research community. We hypothesize that directly isolating disease-relevant changes in RNA from plasma will provide important biomarker candidates for PD. The purpose of this proposal is to develop a comprehensive, plasma-based, exRNA resource that can easily be accessed and utilized by the PD research community. The resulting data will be deposited in the Accelerated Medical Partnerships for Parkinson's disease (AMP-PD) Knowledge Portal. Our Specific Aims are to 1) isolate and characterize RNA alterations from brain-derived EVs from PD patient plasma and age-matched non-PD controls; 2) measure exRNAs isolated from the total EV population in plasma from PD patients and age-matched, non-PD controls; and 3) uniformly and comprehensively sequence the long RNA from captured EVs for data analysis and deposition in AMP-PD Knowledge Portal. The approach proposed in this study is at the leading edge of the EV field, exRNA detection, and analysis. Successful completion of the work will have employed innovative approaches in EV capture, sequencing, and analyses to develop a comprehensive resource that enables future scientific inquiries with broad applicability in biomarker discovery and validation in PD.

项目概要/摘要 帕金森病 (PD) 是一种毁灭性的进行性神经系统疾病，影响着全球 600 万人。缺乏经过验证的帕金森病生物标志物阻碍了预测疾病进展、确定治疗开发新途径以及合理临床试验设计患者分层的进展。细胞外循环 RNA (exRNA) 的捕获和表征方面的最新进展促进了神经系统疾病的疾病机制、治疗靶点的识别和生物标志物的发现，细胞外囊泡 (EV) 可以吸收碎片。细胞货物并进入循环，为监测 PD 患者的 RNA 变化提供了独特的机会，我们的团队帮助成熟了 EV 的捕获和表征，以用于监测疾病 - 使用可以查看货物的策略。总的 EV 群体以及源自受 PD 等疾病影响的特定脑细胞类型的 EV 纵向收集了数千个样本，并对 AMP-PD 队列中数百名患者进行了广泛的表型分析，为开发全面的模型提供了前所未有的机会。资源，可以轻松访问和利用我们渴望直接从血浆中分离出与疾病相关的 RNA 变化，为 PD 提供重要的生物标志物候选物。所得数据将被保存在帕金森病加速医疗合作伙伴关系 (AMP-PD) 知识门户中，我们的具体目标是 1) 分离并表征来自帕金森病患者血浆的脑源性 EV 的 RNA 变化。和年龄匹配的非 PD 对照；2) 测量从 PD 患者和年龄匹配的非 PD 对照血浆中分离出的 exRNA；3) 对捕获的 EV 中的长 RNA 进行统一、全面的测序以进行数据分析本研究提出的方法处于 EV 领域的前沿，exRNA 检测和分析工作的成功完成将采用 EV 捕获、测序和分析方面的创新方法。开发综合资源使未来的科学探究在帕金森病的生物标志物发现和验证中具有广泛的适用性。