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

项目一；

基本信息

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
项目类别：
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

项目摘要

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，我们组建了一支在项目I的才华横溢的团队（孤立或非同伴先天性diaphragmatragmatic疝（CDH）的多基因原因将由主要研究人员Barbara Pober，MD和Jay Wilson，MD。威尔逊博士为先天性diaphragmatragmatic疝的患者构思并培育了最令人印象深刻的后续诊所之一，该诊所已成为全国其他诊所的典范。它的跨学科性质提供了广泛的注意，以满足CDH幸存者的需求，这些CDH幸存者的需求经常患有严重的支气管肺发育异常，并伴随着由食管食道反射引起的喂养障碍，并导致持续的肺损伤，由于饮食困难而不再繁殖，并且由于喂养异常和神经学疾病而无法壮成长。此外，威尔逊博士还负有直接的责任，负责在体外膜氧合（ECMO）以及针对修复隔膜和其他相关先天性异常的多次手术过程中管理这些患者。他与波士顿儿童医院的一组儿科外科医生一起工作，Donahoe博士与Mass Mass General Hospital Hospital for Children Hospital合作。实际上，由于父母的慷慨和寻找这些异常的遗传原因的投资，这两个部位的所有患者都已进入研究。在这项不断扩大的赠款过程中，这两个机构在两个机构中的应计率约为90％。医学博士Barbara Pober博士是CDH研究中世界上主要的遗传学家之一。她亲自表型所有患者，并将其进入一个数据库，她在波士顿儿童医院与丹尼·肖（Danny Shaw）一起设计，并输入了临床数据。她的仔细表型通过每个外科医生定义表型的位置和隔膜缺陷的严重程度的非常精确的文档和严重程度来匹配手术室。 Pober博士与全世界的同事合作。她的同事们掌握的专业人士对我们的多元化家庭的成功应计。她直接根据儿童和大众综合医院的儿童进行适当的确定，收集标本及其适当的支付给马萨诸塞州综合医院的DNA提取DNA以及创建淋巴母细胞或成纤维细胞细胞系，直接监督研究协调员。 Pober博士与Donahoe博士，研究研究员和计划协调员合作，将标本的流动引导到适当的实验室，并收集，解释和整合所得的数据。每个家庭都有多个受影响患者的家庭血统，并尝试记录是否存在血缘关系。在当前赠款间隔的过程中，已经设计了检查近亲家庭的单例的策略，以便检查出通过体面或杂合性丧失（LOH）身份的区域，以了解伴随的拷贝数变体（CNV）。据认为，在LOH地区，CNV的这种巧合发生在约10％的亲密单例中，这使得这种方法值得进行。我们的计划协调员Caroline Coletti M.S.通过管理核心维持标本的流动，并报告了多个站点之间的结果，共同努力实现该计划项目的目标。她和Donahoe博士将与每个项目I，II和III项目的主要研究人员以及核心主管选择合适的研究平台，并收集数据以进行后续存储和解释。他们将在现场或视频会议和计划外部咨询委员会的意见和评估中每两周开会一次。他们还将计划手稿，进度报告和授予续签。