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

基本信息

批准号：
8554393
负责人：
Andrew B West
金额：
$ 29.01万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
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/8554393
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 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 public health relevance screening trafficking urinary

项目摘要

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.

描述（由申请人提供）：通常认识到，与临床人群中与帕金森氏病（PD）相关的疾病进展和生化途径的措施不足，并且缺乏有效的生物标志物受到阻碍，并且预计会继续障碍（成功地妨碍）临床试验，以促进疾病（疾病）。遗传学和病理研究已经确定了与晚期PD相关的几种蛋白质，这些蛋白质提供了对可能对疾病至关重要的途径的见解。但是，由于可易受易感性组织的可用性有限，这些蛋白质在PD病例中很难分析，并且研究通常仅限于验尸后的标本。我们最近的观察结果是，在从人类尿液样品中分离出的外泌体中，可以检测到遗传和病理上与PD连接的其他蛋白质。使用多重质谱方法，我们可以通过临床尿液外泌体样品来量化935种蛋白质，其中140种蛋白质通过途径分析与神经变性有关。 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),为未来LRRK2抑制剂临床试验建立靶向效应的测定法。潜在的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。