Cleft Lip Genetics: A Multicenter International Consortium

唇裂遗传学：多中心国际联盟

• 批准号: 7258364
• 负责人: Andrew C Lidral
• 金额: $ 10.17万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-07 至 2008-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7258364
• 关键词: Affect; Animal Model; Award; Biological Process; Candidate Disease Gene; Child; Chromosome Mapping; Cleaved cell; Cleft Lip; Cleft Palate; Clinical; Collaborations; Colombia; Complex; Congenital Abnormality; Data Analyses; Defect; Development; Developmental Biology; Diagnosis; Disease; Dissection; Environmental Risk Factor; Etiology; Family; Fathers; Finland; Foundations; Genes; Genetic; Genome; Genome Scan; Genotype; Goals; Human Genetics; International; Iowa; Knowledge; Laboratories; Life; Linkage Disequilibrium; Literature; Live Birth; Maps; Molecular; Mothers; Mutation; Nuclear; Numbers; Ohio; Patients; Pennsylvania; Phenotype; Population; Prevalence; Prevention therapy; Recruitment Activity; Relative (related person); Research; Resources; Role; Technology; Testing; Time; Washington; base; career; craniofacial; genetic analysis; genetic linkage analysis; genetic pedigree; genetic variant; genome wide association study; member; orofacial; prevent; skills; tool; trait

DESCRIPTION (provided by applicant): The focus of my research career is to identify the causes of craniofaciai anomalies, which will provide the foundation to develop strategies and therapies to prevent this common group of birth defects. The specific goals of this award are to 1) provide intensive research time in order to accomplish the goals of the research plan; 2) immerse myself in the literature to stay abreast of new discoveries and technologies such that they can be rapidly integrated into this project when warranted; and 3) broaden my expertise in human genetics as well as molecular and developmental biology to allow me to develop a set of life long skills as my career progresses from disease gene identification and molecular characterization, to the development and study of animal models to finally the development and implementation of prevention therapies. Cleft lip with or without cleft palate (CL/P) is a common birth defect. Previous studies have indicated that CL/P is a complex trait that is caused by a combination of genetic and environmental factors. This complexity has limited studies, such that disease mutations have only been identified in one unique family. It is also unlikely that all disease loci have been identified. The overall objective of this project is to identify disease genes involved in nonsyndromic CL/P by applying new multistage linkage and linkage disequilibrium (LD) strategies to affected relative pairs and extended pedigrees. This multistage approach, which has not yet been applied to CL/P, is very powerful in that no prior knowledge about the involved genetic or biological processes is needed. Hypothesis to be tested: Nonsyndromic CLIP is caused by Genetic Variants at one or more loci. To test this hypothesis, CL/P families with both multiple affected members and mother/father and affected child trios will be recruited from a variety of clinical centers. The families will be the basis for initially evaluating candidate genes to test the above hypothesis using the genetic tools of linkage and linkage disequilibrium to reject (exclude) or provide evidence for support (i.e. linkage) the hypotheses. A 10 cM genome-wide screen will also be performed to find additional loci. Positive loci will be further evaluated by a combination of multipoint, multi-locus and TDT/association analyses using more densely spaced markers. It will be through multi-center projects such as this one, in which worldwide collaborations have been established to apply a combination of complimentary genetic strategies, that disease loci for CL/P wilt be identified. Ultimately, this will further the understanding of normal and abnormal craniofacial development, such that therapies to prevent CL/P can be developed and implemented.

描述(申请人提供)：我的研究生涯的重点是找出颅面畸形的原因，这将为制定预防这类常见出生缺陷的策略和治疗方法提供基础。该奖项的具体目标是1)提供密集的研究时间，以实现研究计划的目标；2)沉浸在文献中，与新发现和技术保持同步，以便在必要时能够迅速整合到这个项目中；以及3)拓宽我在人类遗传学以及分子和发育生物学方面的专业知识，使我能够随着职业生涯的进步发展一整套终身技能，从疾病基因鉴定和分子表征，到动物模型的开发和研究，最后是预防疗法的开发和实施。 唇裂伴或不伴腭裂(CL/P)是常见的出生缺陷。以往的研究表明，CL/P是一种复杂的性状，是遗传和环境因素共同作用的结果。这种复杂性限制了研究，以至于只在一个独特的家族中发现了疾病突变。也不太可能确定所有的疾病部位。该项目的总体目标是通过将新的多阶段连锁和连锁不平衡(LD)策略应用于受影响的亲属对和扩大的家系来识别与非综合征CL/P相关的疾病基因。这种尚未应用于CL/P的多阶段方法非常强大，因为不需要关于所涉及的遗传或生物过程的先验知识。 有待检验的假说：非综合征性夹闭是由一个或多个基因座的遗传变异引起的。 为了验证这一假设，有多个受影响成员以及母亲/父亲和受影响儿童三人组的CL/P家庭将从各种临床中心招募。这些家系将作为初步评估候选基因的基础，利用连锁和连锁不平衡的遗传工具来检验上述假说，以拒绝(排除)或提供支持(即连锁)假说的证据。还将进行10厘米宽的基因组筛查，以寻找更多的基因座。阳性基因座将通过多点、多基因座和TDT/关联分析的组合使用更密集的标记进行进一步评估。它将通过多中心项目，如这个项目，在世界范围内建立合作，应用互补的遗传策略的组合，将确定CL/P的疾病位点。最终，这将进一步加深对正常和异常颅面发育的理解，从而可以开发和实施预防CL/P的治疗方法。