Transcriptome in Huntington's disease and Huntington's disease-like 2

亨廷顿病和类亨廷顿病 2 的转录组

基本信息

批准号：
8390995
负责人：
RUSSELL L MARGOLIS
金额：
$ 28.18万
依托单位：
UNIVERSITY OF IOWA
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：
2012-06-01 至 2013-01-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8390995
关键词：
16q Adult Affect American Autopsy Bioinformatics Biological Assay Biological Models Brain Brain region Brodmann&apos s area Chromosomes Data Defect Disease Exons Functional disorder Gene Expression Gene Expression Profile Generations Genes Human Huntington Disease Label Lead Length Methods Molecular Molecular Target Motor Cortex Mus Neurodegenerative Disorders Pathogenesis Pathway interactions Patients Pattern Proteomics Protocols documentation RNA RNA Processing RNA Sequence Analysis RNA Sequences RNA Splicing RNA Transport Relative (related person)Resolution Resources Reverse Transcriptase Polymerase Chain Reaction Risk Role Sampling Spliced Genes System Technology Testing Toxic effect Transcript Transgenes Transgenic Organisms Triplet Multiple Birth Validation base brain tissue density effective therapy frontal lobe genome-wide genome-wide analysis human Huntingtin protein human data improved insight junctophilin mind control mouse model mutant novel novel strategies polyglutamine therapeutic development therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): Huntington's disease (HD) and Huntington's disease-like 2 (HDL2) are remarkably similar autosomal dominant adult onset neurodegenerative disorders, nearly indistinguishable clinically and pathologically. Each disease is ultimately fatal with no effective treatment to stop or slow the relentless progression. HD affects about 30,000 Americans, with a much higher number at risk; HDL2 is rare. The complete explanation for HD and HDL2 pathogenesis remains elusive. A novel strategy for focusing the search for disease mechanisms and therapeutic targets of HD is to determine those points at which the pathogenic pathways of HD and HDL2 converge. A particularly powerful method for implementing this strategy is to compare the transcriptomes of the two diseases. Based on our preliminary evidence, we hypothesize that both abnormal levels of gene expression and abnormal gene splicing will be present in HD and HDL2 and that the sets of these abnormalities will overlap in the two diseases. Here we propose to take advantage of the remarkable similarities of HD and HDL2 to identify convergent pathogenic pathways, via parallel transcriptome characterization of mouse models and human patient samples of HD and HDL2. We propose two specific aims. In aim 1, we will use state of the art exon junction array, RNA sequencing (RNA-Seq), and analytic methods to examine and compare RNA extracted from human HD and HDL2 postmortem brains and mouse models of HD and HDL2 as well as controls. In aim 2, we will experimentally validate expression and splicing abnormalities using high-throughput automated PCR assays and new RNA samples, compare mouse and human data, and use bioinformatics tools to determine common gene sets, pathways, and molecular subnetworks shared by genes showing gene expression or splicing abnormalities in HD and HDL2 brains. We anticipate that the proposed studies will create an extremely valuable resource that will provide a detailed characterization of the HD and HDL2 transcriptomes at an unprecedented resolution and hence fundamentally improve understanding of disease pathophysiology. PUBLIC HEALTH RELEVANCE: Huntington's disease (HD) and Huntington's disease-like 2 (HDL2) are remarkably similar autosomal dominant adult onset neurodegenerative disorders, nearly indistinguishable clinically and pathologically. This project will conduct a comprehensive examination and comparison of HD and HDL2 transcriptomes to identify defects in gene expression and splicing in diseased brains. These studies will lead to a better understanding of HD and HDL2 pathophysiology, and may reveal novel molecular targets and pathways for therapeutic development.

描述（由申请人提供）：亨廷顿病 (HD) 和亨廷顿病样 2 (HDL2) 是非常相似的常染色体显性成人发病神经退行性疾病，在临床和病理上几乎无法区分。每种疾病最终都是致命的，没有有效的治疗方法来阻止或减缓无情的进展。 HD 影响约 30,000 名美国人，其中面临风险的人数要多得多； HDL2 很少见。 HD 和 HDL2 发病机制的完整解释仍然难以捉摸。专注于寻找 HD 疾病机制和治疗靶点的新策略是确定 HD 和 HDL2 致病途径的交汇点。实施这一策略的一个特别有效的方法是比较两种疾病的转录组。根据我们的初步证据，我们假设 HD 和 HDL2 中都会存在基因表达水平异常和基因剪接异常，并且这些异常的集合在这两种疾病中会重叠。在这里，我们建议利用 HD 和 HDL2 的显着相似性，通过 HD 和 HDL2 的小鼠模型和人类患者样本的平行转录组表征来识别趋同的致病途径。我们提出两个具体目标。在目标 1 中，我们将使用最先进的外显子连接阵列、RNA 测序 (RNA-Seq) 和分析方法来检查和比较从人类 HD 和 HDL2 死后大脑、HD 和 HDL2 小鼠模型以及对照中提取的 RNA 。在目标 2 中，我们将使用高通量自动 PCR 测定和新的 RNA 样本来实验验证表达和剪接异常，比较小鼠和人类数据，并使用生物信息学工具来确定显示基因的基因共享的常见基因集、通路和分子子网络HD 和 HDL2 大脑中的表达或剪接异常。我们预计拟议的研究将创造一个极其有价值的资源，以前所未有的分辨率提供 HD 和 HDL2 转录组的详细表征，从而从根本上提高对疾病病理生理学的理解。公共卫生相关性：亨廷顿病 (HD) 和亨廷顿病样 2 (HDL2) 是非常相似的常染色体显性成人发病神经退行性疾病，在临床和病理上几乎无法区分。该项目将对HD和HDL2转录组进行全面检查和比较，以识别患病大脑中基因表达和剪接的缺陷。这些研究将有助于更好地了解 HD 和 HDL2 病理生理学，并可能揭示治疗开发的新分子靶点和途径。