LRRK2 and Other Novel Exosome Proteins in Parkinson's Disease

LRRK2 和其他新型外泌体蛋白在帕金森病中的作用

• 批准号: 8472329
• 负责人: Andrew B West
• 金额: $ 29.3万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8472329
• 关键词: Address; Affect; Age; American; Animal Model; Biochemical Pathway; Biological Assay; Biological Markers; Bladder Control; Cancer Patient; Clinic; Clinical; Clinical Trials; Data; Disease; Disease Progression; Disease susceptibility; Future; Gender; Genetic; Golgi Apparatus; Heterogeneity; Human; Individual; LRRK2 gene; Link; Mass Spectrum Analysis; Measurement; Measures; Meta-Analysis; Monitor; Nerve Degeneration; Neurodegenerative Disorders; Paper; Parkinson Disease; Parkinsonian Disorders; Pathway Analysis; Pathway interactions; Patients; Phosphorylation; Population; Power Sources; Predisposition; Proteins; Proteome; Proteomics; Protocols documentation; Reproducibility; Running; Sample Size; Sampling; Screening procedure; Series; Specimen; Staging; Technology; Therapeutic; Time; Tissues; Urine; Western Blotting; case control; cell motility; cohort; disease diagnosis; high risk; inhibitor/antagonist; innovation; insight; interest; kinase inhibitor; leucine-rich repeat kinase 2; link protein; multicatalytic endopeptidase complex; nervous system disorder; novel; novel marker; novel therapeutics; protein degradation; trafficking; urinary

DESCRIPTION (provided by applicant): It is generally recognized that there are inadequate measures of detecting disease progression and biochemical pathways associated with Parkinson's disease (PD) in clinical populations, and that this lack of effective biomarkers has hindered, and is expected to continue to impede, successful clinical trials for efficacious neuroprotective (disease-retarding or halting) therapeutics. Genetic and pathological studies have identified several proteins linked to late-onset PD, and these proteins have provided insight into pathways that might be central to disease. However, these proteins have been difficult to analyze in PD cases due to the limited availability of disease-susceptible tissue, and studies are usually confined to post-mortem derived specimens. We have made the recent observation that LRRK2, and other proteins linked genetically and pathologically to PD, are detectable in exosomes isolated from human urine samples. Using a multiplex mass spectrometry approach, we can quantify 935 proteins from clinical urine exosome samples, and 140 of these proteins are linked to neurodegeneration by pathway analysis. This proposal seeks to 1) determine whether there are biomarkers associated with PD susceptibility and/or progression in urinary exosome-proteomes derived from PD patients versus controls, and 2) to determine if LRRK2 expression and/or phosphorylation are significantly lowered in the urinary exosomes of individuals treated with the potent LRRK2 kinase inhibitor sunitinib (a multi-kinase inhibitor compound), to establish an assay for on-target effects for future LRRK2 inhibitor clinica trials. Potential biomarkers of interest will be validated in replication cohorts, and the most promising leads will be further explored in future multi-center studies. PUBLIC HEALTH RELEVANCE: Over one-million Americans may be affected with Parkinson's disease, a devastating neurodegenerative disorder for which there is no cure. This proposal will seek out new markers to aid in disease diagnosis and tracking of disease progression, which may directly benefit patients affected with Parkinson's disease and help power future clinical trials for the discovery of new therapeutics.

描述（由申请人提供）：人们普遍认为，在临床人群中检测与帕金森病（PD）相关的疾病进展和生化途径的措施不足，并且有效生物标志物的缺乏已经阻碍并且预计将继续阻碍有效的神经保护（延迟或停止疾病）治疗的临床试验的成功。遗传和病理学研究已经确定了几种与迟发性帕金森病相关的蛋白质，这些蛋白质为了解可能是疾病核心的途径提供了见解。然而，由于疾病易感组织的可用性有限，这些蛋白质在帕金森病病例中很难进行分析，并且 研究通常仅限于尸检标本。我们最近观察到，从人类尿液样本中分离出的外泌体中可以检测到 LRRK2 以及其他与 PD 遗传和病理相关的蛋白质。使用多重质谱方法，我们可以定量临床尿液外泌体样本中的 935 种蛋白质，通过通路分析，其中 140 种蛋白质与神经变性有关。该提案旨在 1) 确定来自 PD 患者与对照的尿液外泌体蛋白质组中是否存在与 PD 易感性和/或进展相关的生物标志物，2) 确定接受强效 LRRK2 激酶抑制剂舒尼替尼（一种多激酶抑制剂化合物）治疗的个体的尿液外泌体中 LRRK2 表达和/或磷酸化是否显着降低， 为未来的 LRRK2 抑制剂临床试验建立一种针对目标效应的测定方法。感兴趣的潜在生物标志物将在复制队列中得到验证，最有希望的线索将在未来的多中心研究中进一步探索。 公共卫生相关性：超过一百万美国人可能患有帕金森病，这是一种无法治愈的破坏性神经退行性疾病。该提案将寻找新的标记物来帮助疾病诊断和跟踪疾病进展，这可能会直接使帕金森病患者受益，并有助于推动未来发现新疗法的临床试验。