Genetic Analysis of Hirschsprung Disease

先天性巨结肠症的遗传分析

• 批准号: 9262256
• 负责人: ARAVINDA CHAKRAVARTI
• 金额: $ 61.75万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2018-04-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262256
• 关键词: 1q21; Affect; Archives; Autistic Disorder; Biochemical Pathway; Biological Assay; Biology; Candidate Disease Gene; Cell Culture Techniques; Cells; ChIP-seq; Collection; Communities; Complex; Congenital Abnormality; Congenital Disorders; Congenital Megacolon; Copy Number Polymorphism; DNA; DNA analysis; Data; Defect; Development; Developmental Biology; Diagnosis; Disease; Embryo; Enhancers; Enteral; Enteric Nervous System; Failure; Family; Formalin; Frequencies; Funding; Future; GDNF gene; GRB10 gene; Ganglia; Gastrointestinal tract structure; Gender; Gene Expression; Gene Family; Genes; Genetic; Genome; Genomic approach; Genotype; Goals; Grant; Hereditary Disease; Histones; Homozygote; Human; Incidence; Information Resources; Institutes; Instruction; Knowledge; Laboratories; Length; Messenger RNA; Modeling; Molecular; Molecular Genetics; Mus; Mutation; NRP1 gene; Neural Crest Cell; Neurons; Neuropilins; Paraffin Embedding; Parents; Pathway interactions; Patient risk; Patients; Phase; Phenotype; Process; RNA; RNA analysis; Recovery; Recruitment Activity; Recurrence; Research; Research Personnel; Research Support; Resources; Risk; Risk Factors; Role; SNP array; Sampling; Signal Pathway; Signal Transduction; Small Interfering RNA; Source; Specific qualifier value; Specificity; Statistical Data Interpretation; Systems Development; Technology; Testing; Therapeutic Intervention; Time; Transcript; Update; Validation; Variant; Zebrafish; base; computer studies; database of Genotypes and Phenotypes; exome sequencing; fetal; gene discovery; gene therapy; genetic analysis; genetic variant; genome wide association study; human disease; improved; interest; knock-down; loss of function; mutant; outcome forecast; plexin; programs; promoter; transcriptome sequencing

PROJECT SUMMARY (See instnjctions}: The proposed research is geared to a near-complete elucidation of the genes, their sequence variants and their biochemical pathways that are mutant and dysregulated In Hirschsprung disease (HSCR); the 'HSCR gene universe.' HSCR is a common neuro-deveiopmental congenital disorder associated with the lack of intramural ganglia along varying lengths of the gastrointestinal tract. The overall goal Is to identify the critical rate-limiting steps in the development of the enteric nervous system (ENS) In humans so that the disease process can be elucidated and, consequently, precise targets for future therapeutic intervention can be. identified. Past research, supported by this grant, has already identified many key molecular genetic features of HSCR. To accomplish the major goals the following aims are being pursued In the next phase: (I) Quantify the mutational burden and effects at the three major signaling pathways (RET, EDNRB, SEMA3) deficient in HSCR; (II) Define the extent, Impact and molecular consequences of large copy number variants In HSCR; (III) Quantify the r6le and impact of common and rare sequence variants in HSCR; (iV) Expand on an existing patient/family collection and maintain a current Information resource for researchers and patients. The general approach being taken Is to use state-of-the-art technologies to screen the genome of HSCR patients, their affected relatives and their parents, using DNA and RNA analyses followed by computational studies, to Identify genes, variants and molecular pathways dysregulated In HSCR. The putative candidate genes are then studied in greater detail in mouse, zebrafish and cell culture models to demonstrate that they indeed contribute to aganglionosis and con-espond to critical rate-limiting steps of the disease. To accomplish these aims, we will also Increase patient and family recruitment from a variety of sources and disseminate our research results in a manner suitable for both the research and HSCR patient communities.

项目总结（见说明）： 这项拟议中的研究是为了接近完整地阐明基因、它们的序列变异和 在先天性巨结肠病（HSCR）中突变和失调的生化途径; 基因宇宙HSCR是一种常见的神经发育先天性疾病，与缺乏 沿着胃肠道的不同长度的壁内神经节沿着。总体目标是确定 在人类肠神经系统（ENS）发育的限速步骤， 可以阐明这一过程，因此可以为未来的治疗干预提供精确的靶点。 鉴定过去的研究，由该基金支持，已经确定了许多关键的分子遗传特征， 的HSCR。为实现主要目标，下一阶段将努力实现以下目标：（一）量化 突变负荷和对三个主要信号通路（RET、EDNRB、SEMA 3）的影响， （II）定义HSCR中大拷贝数变异的程度、影响和分子后果; (III)量化HSCR中常见和罕见序列变体的r6 le和影响; 现有的患者/家庭收集和维护研究人员和患者的最新信息资源。 目前所采取的一般方法是使用最先进的技术来筛选HSCR的基因组 患者，他们受影响的亲属和他们的父母，使用DNA和RNA分析，然后进行计算 研究，以确定基因，变异和分子通路失调的HSCR。假定的候选人 然后在小鼠、斑马鱼和细胞培养模型中更详细地研究基因，以证明它们 确实有助于无神经节细胞症和支持疾病的关键限速步骤。到 为了实现这些目标，我们还将从各种来源增加患者和家属的招募， 以适合研究和HSCR患者社区的方式传播我们的研究成果。