Biomarkers for early intervention in Parkinson disease

帕金森病早期干预的生物标志物

基本信息

批准号：
8727121
负责人：
CLEMENS R SCHERZER
金额：
$ 50.05万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8727121
关键词：
Accounting Antisense RNA Bioenergetics Biological Markers Blood Circulation Brain Case-Control Studies Cerebrospinal Fluid Clinical Trials Code Collection Data Set Development Diagnosis Disabled Persons Disease Early Diagnosis Early Intervention Epigenetic Process Functional RNA Future Gene Expression Gene Expression Profile Genetic Variation Health Human Individual Knowledge Lasers Link Massive Parallel Sequencing Measures Motor Movement National Institute of Neurological Disorders and Stroke Neurons Onset of illness Parkinson Disease Participant Pathogenesis Pathology Patient Care Patients Pharmaceutical Preparations Phase II Clinical Trials Physiology Process Proteins Public Health RNA Research Infrastructure Research Personnel Shapes Symptoms Therapeutic Time Translating Translations Validation base biobank clinical phenotype cost digital disorder control dopaminergic neuron handicapping condition innovation neuropathology novel prevent programs public health relevance public-private partnership reconstruction safety testing therapy design

项目摘要

DESCRIPTION (provided by applicant): No cures exist, but the number of Parkinson's patients is expected to nearly double to 9.3 million in 2030. Two roadblocks impede progress on disease-modifying therapeutics. Current clinical trials are handicapped by late diagnosis, relying on impaired movements that occur when underlying neuropathology has far advanced. Moreover, in phase II clinical trials, testing safety and tolerability of a compound is straightforward, but drug effects on the underlying disease processes cannot be detected by current symptom-based measures. Here we propose a specific and a general strategy to overcome these roadblocks. More than 90,000 non-protein coding, regulatory RNAs may account for the complexity of the human brain in health and disease. Thousands of these previously hidden RNAs abound in dopaminergic neurons and regulate Parkinson's gene expression and bioenergetics processes involved in the disease onset. Regulatory RNAs integrate environmental, epigenetic, and genetic variation and directly reflect altered physiology without translation into protein. This offers a potentially ground breaking opportunity for biomarker development. Initially, we will systematically delineate all non-coding RNAs associated with incipient Parkinson's neuropathology in dopamine neurons laser-captured from 100 human brains using massively parallel sequencing and unlimited transcriptome reconstruction. Then, we will translate regulatory RNAs linked to the earliest neuropathological processes into digital biomarkers detectable in bloodstream and cerebrospinal fluid of 242 and 167 subjects, respectively. To build a generally useful express lane for biomarker development we propose a Harvard-NINDS partnership. It will leverage an unparalleled infrastructure and deliver a longitudinal Parkinson's biobank -- a catalytic, open platform for jump-starting the discovery and validation of PD biomarkers. Ancillary cerebrospinal fluid collection will be performed in the Harvard NeuroDiscovery Center Biomarker Study, a longitudinal, case-control study that already tracks clinical phenotypes and linked biospecimens of >1,886 individuals with Parkinson's disease and controls. This study will discover and translate viable biomarkers for the early detection of Parkinson's disease processes and contribute to a generally useful express lane for biomarkers development.

描述（由申请人提供）：尚无治愈方法，但预计到 2030 年帕金森病患者数量将增加近一倍，达到 930 万。有两个障碍阻碍了疾病缓解疗法的进展。目前的临床试验因诊断较晚而受到阻碍，依赖于当潜在的神经病理学进展已很严重时发生的运动受损。此外，在 II 期临床试验中，测试化合物的安全性和耐受性很简单，但目前基于症状的措施无法检测药物对潜在疾病过程的影响。在这里，我们提出了克服这些障碍的具体和总体策略。超过 90,000 个非蛋白质编码、调节性 RNA 可能解释了人脑在健康和疾病方面的复杂性。数以千计的这些先前隐藏的 RNA 大量存在于多巴胺能神经元中，并调节帕金森病的基因表达和与疾病发作有关的生物能过程。调节性 RNA 整合了环境、表观遗传和遗传变异，直接反映生理变化，无需翻译成蛋白质。这为生物标志物的开发提供了潜在的突破性机会。首先，我们将使用大规模并行测序和无限转录组重建，从 100 个人脑激光捕获的多巴胺神经元中系统地描述与早期帕金森氏症神经病理学相关的所有非编码 RNA。然后，我们将把与最早的神经病理过程相关的调节 RNA 转化为可分别在 242 名和 167 名受试者的血液和脑脊液中检测到的数字生物标志物。为了建立一条普遍有用的生物标志物开发快速通道，我们提议建立哈佛-NINDS 合作伙伴关系。它将利用无与伦比的基础设施并提供纵向帕金森氏生物库——一个催化、开放的平台，用于启动帕金森氏症生物标志物的发现和验证。辅助脑脊液收集将在哈佛神经发现中心生物标志物研究中进行，这是一项纵向病例对照研究，该研究已经跟踪了超过 1,886 名帕金森病患者和对照患者的临床表型和生物样本。这项研究将发现并转化用于早期检测帕金森病过程的可行生物标志物，并为生物标志物开发提供普遍有用的快速通道。