Program Project: GENE MUTATION AND RESCUE IN HUMAN DIAPHRAGMATIC HERNIA

计划项目：人类膈疝的基因突变与挽救

• 批准号: 8079810
• 负责人: PATRICIA K DONAHOE
• 金额: $ 158.49万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8079810
• 关键词: Program; Project; GENE; MUTATION; RESCUE; Program; Project; GENE; MUTATION; RESCUE

DESCRIPTION (provided by applicant): In the quest to unravel the etiology of Congenital Diaphragmatic Hernia (CDH), a prevalent (1:2500 live births) high impact (50% mortality with high morbidity) birth defect with phenotypic and genetic complexity, we are combining novel and traditional investigative strategies to one of the largest cohort of human patients with CDH. Collectively, we are employing molecular genetic, molecular cytogenetic, genomic, developmental, bioinformatic, and stem cell strategies along with the use of multiple model organisms. The strategies that we employ can serve as a template for identifying genes in pathways responsible not only for CDH, but for additional congenital anomalies, as well. The foundation of our work is the Infrastructure developed for ascertaining and recruiting almost all patients with CDH from two academic tertiary pediatric surgical centers, Massachusetts General Hospital (MGH) and Children's Hospital Boston (CHB), each offering state of the art medical, surgical, and genetic diagnosis, and management. Patients and families with CDH are interviewed comprehensively by study staff and carefully phenotyped by a senior geneticist; biological samples are obtained using sensitive protocols adapted for infants and children from each proband and from as many family members as possible, and are banked for proposed iterative genetic studies. Gene candidates are selected for sequencing when there is convergence from multiple lines of inquiry [i.e., copy number variations (CNVs) detected on array Comparative Genomic Hybridization (aCGH) or Single Nucleotide Polymorphism (SNP) arrays, genes in shared intervals detected on linkage analysis in affected belonging to multiplex CDH families, expressed genes in the developing primordial diaphragm, and bioinformatic algorithms that prioritize multiple candidate variants detected by the aforementioned platforms and from annotation of animal models with diaphragm defects]. The functional significance of the most promising candidates is subsequently assessed in multiple animal models. The evolution of available sequencing capabilities to lower costs opens the door to examine the multiple genes or polygeneity that we now know will contribute to a birth defect phenotype such as CDH. Given the national and International outreach and reputation of our genetic partnerships and the strength of the voluntary support network provided by the exceptional parents of patients with CDH, the study has extended beyond our two institutions to ascertain a number of seminal multiplex kindreds, including both consanguineous and non-consanguineous families, from the U.S. and internationally. RELEVANCE: The overarching goal of this study is to converge the multiple genes detected by these complementary approaches into cogent molecular pathways that will reveal polygeneic defects in the pathways and point toward potential treatment paradigms to prevent or alleviate this mortal or morbid congenital anomaly. Further, the methods devised for this study of CDH may have broader implications across other congenital anomalies.

描述（由申请人提供）：为了揭示先天性diaphragmatic疝气的病因（CDH），这是一种普遍的（1：2500 Live Births）高影响力（50％死亡率具有高发病率），具有表型和遗传复杂性，我们将小说和传统的研究策略与CODHORT CDH的一员结合起来，将其结合在一起。总体而言，我们使用分子遗传，分子细胞遗传学，基因组，发育，生物信息学和干细胞策略以及使用多种模型生物。我们采用的策略可以用作模板，以识别不仅负责CDH的途径中的基因，而且还可以识别其他先天性异常。 我们工作的基础是用于确定和招募来自两个学术三级儿科手术中心，马萨诸塞州综合医院（MGH）和波士顿儿童医院（CHB）的基础设施，几乎所有CDH患者，每个患者均提供最先进的医学，外科手术，外科手术，遗传诊断和管理。患者和CDH的患者接受研究人员的全面采访，并由高级遗传学家仔细表现出来。使用适合于每个概率的婴儿和儿童以及来自尽可能多的家庭成员的敏感方案获得生物样品，并进行了依靠的迭代遗传研究。当从多种探究线[即，在阵列比较基因组杂交（ACGH）或单核苷酸多态性（SNP）阵列（SNP）阵列中检测到的多种拷贝数变化（CNV）时，选择基因候选物进行测序。 开发原始diaphragm和生物信息学算法，以优先考虑多个候选变体 通过上述平台检测到来自具有隔膜缺陷的动物模型的注释]。随后在多个动物模型中评估了最有前途的候选人的功能意义。 可用的测序能力降低成本的演变为检查多元基因或多元政府的大门打开了我们现在所知道的多元基因或多光学性，这将有助于诸如CDH之类的先天缺陷表型。 鉴于我们的遗传伙伴关系的国家和国际宣传以及CDH患者杰出父母提供的自愿支持网络的实力，该研究已超越了我们的两个机构，以确定许多开创性的多元型物品，包括来自美国和美国国际上的cangunance乱和非传统家庭。 相关性：这项研究的总体目标是将这些互补方法检测到的多个基因汇聚为可结合的分子途径，这些途径将揭示途径中的多元缺陷，并指向潜在的治疗范式，以预防或减轻这种致命或病态的先天性异常。此外，为这项CDH研究设计的方法可能在其他先天性异常中具有更广泛的含义。