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.

项目总结/摘要 帕金森病（PD）是一种破坏性和进行性神经系统疾病，影响全球600万人。缺乏有效的PD生物标志物阻碍了预测疾病进展、确定治疗开发的新途径和患者分层以实现合理的临床试验设计。细胞外循环RNA（exRNA）的捕获和表征的最新进展刺激了神经系统疾病中疾病机制的鉴定、治疗靶点参与和生物标志物的发现。细胞外囊泡（EV）可以携带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。我们的团队已经帮助成熟的捕获和表征电动汽车的部署监测疾病-使用的策略，可以看看货物从总电动汽车人口以及电动汽车来源于特定的脑细胞类型的疾病，如PD。数千份样本的纵向收集，以及来自AMP-PD队列中数百名患者的广泛表型分析，为开发PD研究社区可以轻松访问和利用的综合资源提供了前所未有的机会。我们假设直接从血浆中分离出疾病相关的RNA变化将为PD提供重要的生物标志物候选物。该提案的目的是开发一种全面的、基于血浆的exRNA资源，该资源可以很容易地被PD研究界访问和利用。最终的数据将存储在帕金森病加速医疗合作伙伴关系（AMP-PD）知识门户网站中。我们的具体目的是1）从来自PD患者血浆和年龄匹配的非PD对照的脑源性EV分离和表征RNA改变; 2）测量从来自PD患者和年龄匹配的非PD对照的血浆中的总EV群体分离的exRNA;和3）对来自捕获的EV的长RNA进行均匀和全面的测序，用于数据分析和在AMP-PD知识门户中的沉积。本研究中提出的方法处于EV领域、exRNA检测和分析的前沿。这项工作的成功完成将采用EV捕获，测序和分析的创新方法，以开发一个全面的资源，使未来的科学调查在PD的生物标志物发现和验证方面具有广泛的适用性。