Chemical genomic profiling for hereditary dystonia

遗传性肌张力障碍的化学基因组分析

基本信息

批准号：
8033260
负责人：
David Cristopher Bragg
金额：
$ 8.67万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2012-05-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8033260
关键词：
ATP phosphohydrolase Address Adolescence Affect Agonist Aldehydes Basal Ganglia Biological Assay Brain Categories Cell Death Cells Cellular Assay Chemicals Clinical Codon Nucleotides Collecting Cell Collection Communities Computer software Cultured Cells Data Data Analyses Databases Defect Development Disease Dominant-Negative Mutation Dystonia Endoplasmic Reticulum Equipment and supply inventories FDA approved Fibroblasts Functional disorder GAG Gene Gene Chips Gene Cluster Gene Expression Gene Expression Profile Gene Expression Profiling General Hospitals Genes Genomics Genotype Glutamic Acid Goals Harvest Hereditary Dystonia Human Human Genome Individual Inherited Institutes Investigational New Drug Application Label Laboratories Lead Ligands Link Malignant Neoplasms Maps Massachusetts Metabolic Diseases Molecular Chaperones Molecular Profiling Movement Disorders Muscle Contraction Neurodegenerative Disorders Pathogenesis Pathway interactions Patients Pattern Pharmaceutical Chemistry Pharmaceutical Preparations Phenocopy Posture Primary Dystonias Proteins RNA Relative (related person)Reporter Reporting Research Safety Smooth Muscle Structure Surveys TOR1A gene Testing Therapeutic TorsinA Transcript Vendor base clinical practice comparative efficacy design drug candidate early onset genetic analysis genome-wide hospital analysis insight member motor impairment mutant novel novel strategies pre-clinical public health relevance research study small molecule tool

项目摘要

DESCRIPTION (provided by applicant): Early onset (DYT1) dystonia is a hereditary movement disorder involving severe motor impairment believed to reflect a dysfunction within the basal ganglia. Affected individuals develop sustained, involuntary muscle contractions and twisted postures for which few treatment options exist. Most cases are linked to a heterozygous codon deletion which removes a glutamic acid from the carboxy terminus of the encoded protein, torsinA. TorsinA is thought to function within the endoplasmic reticulum (ER) as a molecular chaperone within the secretory pathway. Multiple studies suggest that DYT1 pathogenesis reflects a loss of torsinA function, possibly due to dominant negative effects of the mutant protein. We recently performed a target-based screen that identified a set of small molecule ligands for torsinA, one of which rescues a functional defect in DYT1 cells. This compound is a novel aldehyde synthesized by an academic laboratory and not yet FDA-approved. In this project we propose to use this compound as a probe to find other, known FDA-approved drugs which mimic its effects. If such drugs exist, they could potentially be moved into human trials for dystonia more quickly as they are already approved for clinical use. We will first perform a genomewide expression analysis on primary fibroblasts from DYT1 patients and control in the presence or absence of our lead compound. These gene signatures will be used to query a new database, the Connectivity Map (CMap). CMap was created by obtaining gene expression signatures from cultured cells treated individually with a large collection of known drugs. The database software will allow us to seek drugs predicted to phenocopy our test compound and/or reverse the gene expression profile in untreated DYT1 cells. We will further analyze the gene expression results using Gene Set Enrichment Analysis (GSEA) to identify functional pathways that may be differentially regulated in DYT1 cells relative to controls. We will obtain any drugs identified by CMap as well as ones known to act on targets and/or pathways implicated by the GSEA analysis and compare the new candidates to our test compound in a DYT1 cellular assay. To our knowledge, this analysis would be the first transcriptional profile of human DYT1 cells ever performed and would take advantage of the large inventory of primary dystonia patient cells collected by our team. The results may offer new insight into DYT1 pathogenesis by revealing cellular pathways perturbed by the mutant protein while also seeking new candidates to treat dystonia. PUBLIC HEALTH RELEVANCE: Early onset (DYT1) dystonia is a crippling movement disorder that typically begins during adolescence. Although current therapeutic options are limited, the normal brain structure and absence of cell death observed in affected individuals suggest that the disease could be drug treatable. In this project we propose a novel strategy to find new drug candidates for dystonia that combines (1) genomewide expression profiling of primary DYT1 patient vs. control cells; and (2) a powerful new discovery tool, the Connectivity Map, that links gene expression signatures to specific known drugs.

描述（由申请人提供）：早期发作（DYT1）肌张力障碍是一种遗传运动障碍，涉及严重运动障碍，被认为反映了基底神经节内的功能障碍。受影响的个体会产生持续的，非自愿的肌肉收缩和几乎没有治疗选择的扭曲姿势。大多数情况与杂合密码子缺失有关，该密码子缺失从编码蛋白Torsina的羧基末端去除谷氨酸。人们认为Torsina在内质网中（ER）在分泌途径内的分子伴侣中起作用。多项研究表明，DYT1发病机理反映了躯干功能的丧失，这可能是由于突变蛋白的主要负面影响所致。我们最近进行了一个基于目标的屏幕，该屏幕鉴定了一组小分子配体用于Torsina，其中之一挽救了Dyt1细胞中的功能缺陷。该化合物是由学术实验室且尚未批准的一种新颖的醛合成。在这个项目中，我们建议将该化合物用作探针，以找到模仿其效果的其他已知的FDA批准药物。如果存在此类药物，则可能会更快地将它们转入人体试验中，因为它们已经被批准用于临床使用。我们将首先对DYT1患者的原代成纤维细胞进行全基因组表达分析，并在存在或不存在铅化合物的情况下对照。这些基因签名将用于查询新的数据库，即连接图（CMAP）。 CMAP是通过从用大量已知药物单独处理的培养细胞中获得基因表达信号而创建的。该数据库软件将使我们能够寻求预测的药物为我们的测试化合物和/或逆转未处理的dyt1细胞中的基因表达谱。我们将使用基因集富集分析（GSEA）进一步分析基因表达结果，以鉴定相对于对照组中DYT1细胞中可能受到差异调节的功能途径。我们将获得通过CMAP鉴定的任何药物，以及已知对GSEA分析涉及的靶标和/或途径作用的药物，并将新候选物与DYT1细胞分析中的测试化合物进行比较。据我们所知，这种分析将是有史以来人类Dyt1细胞的第一个转录概况，并将利用我们团队收集的原发性肌张力障碍患者细胞的大量库存。结果可能通过揭示突变蛋白扰动的细胞途径，同时还寻求治疗肌张力障碍的新候选者，从而为DYT1发病机理提供了新的见解。公共卫生相关性：早期发作（DYT1）肌张力障碍是一种残酷的运动障碍，通常在青春期开始。尽管当前的治疗选择是有限的，但是受影响的个体中观察到的正常大脑结构和细胞死亡的缺失表明该疾病可以治疗。在这个项目中，我们提出了一种新的策略，以找到肌张力障碍的新药候选者，该肌张力障碍（1）（1）原发性DYT1患者与对照细胞的全基因组表达分析；（2）一种强大的新发现工具，即连接图，将基因表达签名与特定已知药物联系起来。