Genetic Analysis of Hirschsprung Disease

先天性巨结肠症的遗传分析

• 批准号: 8819621
• 负责人: ARAVINDA CHAKRAVARTI
• 金额: $ 66.44万
• 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 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8819621
• 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; Data; Defect; Development; Developmental Biology; Disease; Embryo; Enhancers; Enteral; Enteric Nervous System; Failure; Family; Formalin; Frequencies; Funding; Future; GDNF gene; GRB10 gene; Ganglia; Gastrointestinal tract structure; Gender; Gene Expression; Genes; Genetic; Genome; Genomic approach; Genotype; Goals; Grant; 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; Recovery; Recurrence; Relative (related person); Research; Research Personnel; Research Support; Resources; Risk; Risk Factors; Role; Sampling; Signal Pathway; Signal Transduction; Small Interfering RNA; Source; Specific qualifier value; Specificity; Staging; Technology; Testing; Therapeutic Intervention; Time; Tissues; Transcript; Update; Validation; Variant; Zebrafish; abstracting; base; computer studies; database of Genotypes and Phenotypes; disease diagnosis; exome sequencing; fetal; gene discovery; gene therapy; genetic analysis; genetic variant; genome wide association study; human disease; improved; interest; loss of function; mutant; nervous system development; outcome forecast; 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.

项目摘要（请参阅Instnjctions}： 拟议的研究旨在几乎完全阐明基因，其序列变体和 他们的生化途径在赫希斯普伦疾病（HSCR）中是突变和失调的突变途径； 'hscr 吉恩宇宙。 HSCR是与缺乏有关 沿胃肠道的不同长度的壁内神经节。总体目标是确定关键 人类肠神经系统（ENS）发展的限制步骤，以便该疾病 可以阐明过程，因此可以为将来的治疗干预措施提供精确的目标。 确定。在这笔赠款支持下的过去研究已经确定了许多关键的分子遗传特征 HSCR。为了实现主要目标，下一阶段正在实现以下目标：（i）量化 三个主要信号通路（RET，EDNRB，SEMA3）的突变负担和影响不足 HSCR; （ii）定义大型拷贝数变体在HSCR中的程度，影响和分子后果； （iii）量化HSCR中常见和稀有序列变体的R6LE和影响； （iv）扩展 现有的患者/家庭收集并为研究人员和患者维护当前的信息资源。 所采用的一般方法是使用最先进的技术来筛选HSCR的基因组 患者，受影响的亲戚和父母，使用DNA和RNA分析，然后进行计算 研究，以鉴定HSCR中失调的基因，变异和分子途径。推定的候选人 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 确实有助于促进性疾病，并与疾病的关键限制步骤相对应。到 完成这些目标，我们还将从各种来源增加患者和家庭招聘 以适合研究和HSCR患者社区的方式传播我们的研究。