A Next Generation of Biomarkers for Incipient Huntington Disease

早期亨廷顿病的下一代生物标志物

基本信息

批准号：
8920171
负责人：
CLEMENS R SCHERZER
金额：
$ 50.58万
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：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8920171
关键词：
Age Base Pairing Biochemical Biological Assay Biological Markers Blood Blood specimen Cataloging Catalogs Cells Cerebrospinal Fluid Cessation of life Clinic Clinical Clinical Trials Design Data Set Development Diagnostic Disease Early Intervention Future Gene Expression Genetic Risk Health Human Huntington Disease Individual Life Link Liquid substance Massive Parallel Sequencing Messenger RNA MicroRNAs Molecular Monitor National Institute of Neurological Disorders and Stroke Neurons North America Onset of illness Peripheral Persons Pharmaceutical Preparations Process Progressive Disease RNA Reporter Research Infrastructure Research Personnel Resolution Resource Development Resources Running Staging Symptoms Time Transcript Translating Translations analog biobank burden of illness clinical phenotype cost design digital effective intervention human Huntingtin protein human disease innovation molecular marker mutant next generation next generation sequencing novel prevent repository sex

项目摘要

DESCRIPTION (provided by applicant): A Next Generation of Biomarkers for Incipient Huntington's Disease Early intervention will be instrumental to slow or even prevent the clinical manifestations of Huntington's disease (HD). To enable early intervention, biomarkers are needed that track disease processes before devastating symptoms develop. Multiple lines of evidence implicate mutant huntingtin-induced transcriptional dysregulation of messenger and microRNAs in the disease pathobiology. Although HD symptoms reflect preferential neuronal death mutant huntingtin is ubiquitously expressed and biochemical changes can be found in peripheral cells and fluids. This creates an opportunity for translation into clinically useful biomarkers. We hypothesize that microRNAs and messenger RNAs can serve as cerebrospinal fluid and blood markers that track the progressive disease process --- before the clinical phenotype manifests. Next- generation sequencing of microRNA transcripts offers advantageous precision, dynamic range, and sensitivity compared to traditional analog gene expression platforms. Here we will use massively parallel sequencing to discover and independently replicate all known and novel microRNA transcripts associated with pre-manifest HD in cerebrospinal fluid and blood of 100 cases and 100 age- and sex-matched controls. Replicated cerebrospinal fluid and blood microRNA markers will then be translated onto a digital, go-to-the-clinic assay platform. Furthermore, messenger RNAs previously linked to manifest HD will be evaluated for use as potential peripheral biomarkers in individuals at pre-manifest disease stages. To build a generally useful launch platform for biological markers of incipient HD we will establish a cerebrospinal fluid and blood RNA bio-bank linked to PREDICT-HD -- a national resource for the development of molecular markers designed to guide treatment of onset disease. This study will discover and replicate bio-fluid transcripts potentialy useful for monitoring disease processes prior to the onset of clinical symptoms. If confirmed, this next generation of biomarkers will transform clinical trial design and will enable earlier and more effective intervention.

描述（由申请人提供）：早期亨廷顿病的下一代生物标志物早期干预将有助于减缓甚至预防亨廷顿病（HD）的临床表现。为了实现早期干预，需要生物标志物在破坏性症状出现之前跟踪疾病过程。多种证据表明疾病病理学中亨廷顿蛋白突变体诱导的信使和 microRNA 转录失调。尽管亨廷顿舞蹈症症状反映了神经元优先死亡，但亨廷顿蛋白突变体普遍表达，并且在外周细胞和体液中可以发现生化变化。这为转化为临床有用的生物标志物创造了机会。我们假设 microRNA 和信使 RNA 可以作为脑脊液和血液标记物，在临床表型出现之前追踪疾病的进展过程。与传统的模拟基因表达平台相比，新一代 microRNA 转录本测序提供了优越的精度、动态范围和灵敏度。在这里，我们将使用大规模并行测序来发现并独立复制 100 例病例和 100 名年龄和性别匹配对照的脑脊液和血液中与预表现 HD 相关的所有已知和新型 microRNA 转录本。然后，复制的脑脊液和血液 microRNA 标记将被翻译到数字化的临床检测平台上。此外，之前与明显 HD 相关的信使 RNA 将被评估，以用作处于明显疾病阶段的个体的潜在外周生物标志物。为了建立一个普遍有用的早期 HD 生物标志物启动平台，我们将建立一个与 PREDICT-HD 相关的脑脊液和血液 RNA 生物库，这是一个用于开发旨在指导发病疾病治疗的分子标志物的国家资源。这项研究将发现并复制生物体液转录物，可能有助于在临床症状出现之前监测疾病过程。如果确认的话，这下一代生物标志物将改变临床试验设计，并使更早、更多的临床试验成为可能有效干预。