PROJECT I; POLYGENIC CAUSES of ISOLATED and NON-SYNDROMIC CONGENITAL

项目一；

• 批准号: 8143184
• 负责人: PATRICIA K DONAHOE
• 金额: $ 50.03万
• 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/8143184
• 关键词: Address; Advisory Committees; Affect; Archives; Biological; Boston; Bronchopulmonary Dysplasia; Candidate Disease Gene; Caring; Cell Line; Child; Childhood; Clinic; Clinical Data; Collaborations; Comorbidity; Congenital diaphragmatic hernia; Consanguinity; Country; Custom; DNA; DNA Library; Data; Databases; Defect; Diaphragmatic Hernia; Disease; Doctor of Medicine; Documentation; Enrollment; Etiology; Evaluation; Extracorporeal Membrane Oxygenation; Failure to Thrive; Family; Fibroblasts; Funding; Future; Gastroesophageal reflux disease; Gene Mutation; General Hospitals; Genes; Genetic; Genetic Variation; Genomics; Glean; Goals; Grant; Head; Hearing; Heart; Human; Institution; International; Investments; Laboratories; Lead; Location; Loss of Heterozygosity; Manuscripts; Maps; Massachusetts; Middle East; Modeling; National Institute of Child Health and Human Development; Nature; Operating Rooms; Operative Surgical Procedures; Parents; Patients; Pediatric Hospitals; Phenotype; Principal Investigator; Progress Reports; Recording of previous events; Recruitment Activity; Reporting; Research; Research Infrastructure; Respiratory Diaphragm; Severities; Site; Source; Specimen; Surgeon; Survivors; Tissues; Variant; Work; Workplace; base; cohort; design; exome; feeding; follow-up; gene discovery; genetic linkage analysis; genetic pedigree; kindred; lung injury; lymphoblast; meetings; member; nervous system disorder; next generation; novel; programs; repaired; sample collection; tool

To address the Specific Aims of the Program Project we have assembled a talented team in PROJECT I (Polygenic Causes of Isolated or Non-Syndromic Congenital Diaphragmatic Hernia (CDH) will be Informed by Rare Monogenic CDH) headed by Principal Investigators Barbara Pober, MD, and Jay Wilson,MD. Dr. Wilson has conceived and nurtured one of the most impressive follow up clinics for patients with congenital diaphragmatic hernia which has served as a model for other clinics around the country. Its interdisciplinary nature provides a broad spectrum of care to address the needs of CDH survivors who often have severe bronchopulmonary dysplasia accompanied by feeding disorders caused by gastroesophageal reflux and contributing to continued lung injury, failure to thrive because of feeding difficulties, and associated hearing abnormalities and neurological disorders particularly in those patients with syndromic CDH. Dr. Wilson, in addition, has direct responsibilities for managing these patients while on extracorporeal membrane oxygenation (ECMO) and during their multiple surgical procedures directed toward repair of the diaphragm and other associated congenital anomalies. He works with a team of pediatric surgeons at the Children's Hospital Boston and Dr. Donahoe works with the team at the Mass General Hospital for Children. Virtually all of the patients at both sites have been enrolled into the study due to the generosity of their parents and their investment In finding the genetic causes of these anomalies. This has resulted In an approximately ninety percent accrual rate at both institutions over the course of this expanding grant. Dr. Barbara Pober, M.D., is one of the leading geneticists in the world in the study of CDH. She personally phenotypes all of the patients and enters them into a database which she designed with Danny Shaw at the Children's Hospital Boston, into which clinical data is entered. Her careful phenotyping is matched in the operating room by the very precise documentation of the location and the severity of the diaphragm defect by each surgeon to define the phenotype. Dr. Pober has worked with her colleagues all over the world; the professional regard with which she is held by her colleagues has lead to our successful accrual of informative multiplex families. She directly supervises the study coordinators based both at Children's and at Mass General Hospital for Children for appropriate ascertainment, collection of specimens and their proper disbursement to the Massachusetts General Hospital for the extraction of DNA, and the creation of lymphoblast or fibroblast cell lines. Dr. Pober works with Dr. Donahoe, the research fellows, and the Program Coordinator to direct the flow of specimens to appropriate laboratories and to collect, interpret, and integrate resulting data. Family pedigrees are drawn for each family with multiple affected patients with CDH and attempts are made to document if consanguinity is present. During the course of the present grant interval, strategies to examine singletons from consanguineous families have been devised so that regions showing identity by decent or loss of heterozygosity (LOH) are examined for concomitant copy number variants (CNVs). It Is thought that this coincidence of CNVs in regions of LOH occurs in about ten percent of the consanguineous singletons which makes this approach worthwhile to undertake. Caroline Coletti, M.S., our program coordinator, maintains the flow of specimens via the administration core and reports results between the multiple sites working together to achieve the goals of this Program Project. She and Dr. Donahoe will work with the Principal Investigators of each Project I, II, and III, and the Core Directors to select the appropriate platform for study and to collect data for subsequent storage and interpretation. They will meet every two weeks on site or by video conferencing and plan External Advisory Committee input and evaluation. They will also plan manuscripts, progress reports, and grant renewals.

为了解决该计划项目的具体目标，我们在项目I（孤立或非综合征型先天性膈疝（CDH）的多基因原因将由罕见的单基因CDH告知）中组建了一支才华横溢的团队，由首席研究员Barbara Pober，MD和Jay Wilson，MD领导。 博士威尔逊构思和培育了一个最令人印象深刻的后续诊所的患者先天性腹股沟疝，已作为一个模式，为其他诊所在全国各地。它的跨学科性质提供了广泛的护理，以满足CDH幸存者的需求，这些幸存者通常患有严重的支气管肺发育不良，伴有胃食管反流引起的进食障碍，并导致持续的肺损伤，由于进食困难而无法茁壮成长，以及相关的听力异常和神经系统疾病，特别是在综合征型CDH患者中。此外，Wilson博士还直接负责管理这些患者，同时进行体外膜肺氧合（ECMO）以及针对膈肌修复和其他相关先天性异常的多种外科手术。他与波士顿儿童医院的一个儿科外科医生团队合作，多纳霍博士与马萨诸塞州儿童综合医院的团队合作。由于父母的慷慨以及他们在寻找这些异常的遗传原因上的投资，两个研究中心几乎所有的病人都被纳入了这项研究。这导致了在这两个机构在这一不断扩大的赠款过程中，约百分之九十的应计率。 博士Barbara Pober，医学博士，是世界上研究先天性髋关节脱位的主要遗传学家之一。她 她亲自对所有患者进行表型分析，并将其输入到一个数据库中，该数据库是她与波士顿儿童医院的丹尼·肖设计的，临床数据被输入其中。在手术室中，每位外科医生都对横膈膜缺损的位置和严重程度进行了非常精确的记录，以确定表型，与她仔细的表型相匹配。Pober博士与她的同事在世界各地工作;她的同事们对她的专业态度使我们成功地积累了信息丰富的多元化家庭。她直接监督儿童医院和马萨诸塞州儿童综合医院的研究协调员进行适当的确认、标本收集并将其适当地分配给马萨诸塞州综合医院，以提取DNA，并建立淋巴母细胞或成纤维细胞系。Pober博士与Donahoe博士、研究员和项目协调员合作，将标本流引导到适当的实验室，并收集、解释和整合结果数据。 对每个家族中有多个CDH患者的家庭进行家系分析，并试图记录是否存在血缘关系。在本研究期间，我们设计了一些策略来检查来自血缘家庭的单胎，以便对通过杂合性缺失（洛）显示身份的区域进行伴随拷贝数变异（CNVs）的检查。据认为，这种在洛区域的CNV的重合发生在大约10%的血缘单基因中，这使得这种方法值得进行。 卡罗琳·科莱蒂，理学硕士，我们的项目协调员，通过管理核心维护标本的流动，并报告多个地点之间的结果，共同努力实现本项目的目标。 她和多纳霍博士将与每个项目I、II和III的主要研究者以及核心总监合作，选择适当的研究平台并收集数据以供后续存储和解释。他们将每两周在现场或通过视频会议举行一次会议，并计划外部咨询委员会的投入和评价。他们还将计划手稿，进度报告和赠款更新。