Cleft Lip Genetics: A Multicenter International Consortium

唇裂遗传学：多中心国际联盟

• 批准号: 7092640
• 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 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7092640
• 关键词: Colombia; Scandinavian country; United States; cleft lip; cleft palate; clinical research; disease /disorder etiology; family genetics; gene mutation; genetic markers; genetic screening; genome; genotype; high throughput technology; human subject; linkage disequilibriums; linkage mapping; patient oriented research

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（由申请人提供）：我的研究生涯的重点是确定颅面异常的原因，这将为制定预防这一常见出生缺陷的策略和疗法提供基础。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，以跟上新的发现和技术，以便在必要时能够迅速融入该项目;和3）拓宽了我在人类遗传学以及分子和发育生物学方面的专业知识，使我能够在职业生涯中从疾病发展到终身技能。从基因鉴定和分子表征，到动物模型的开发和研究，最后到预防疗法的开发和实施。 唇裂伴或不伴腭裂（CL/P）是一种常见的出生缺陷。以往的研究表明，CL/P是一个复杂的性状，是由遗传和环境因素的组合。这种复杂性限制了研究，例如仅在一个独特的家族中发现了疾病突变。也不可能确定所有的疾病位点。该项目的总体目标是通过对受影响的亲属对和扩展谱系应用新的多阶段连锁和连锁不平衡（LD）策略来识别参与非综合征性CL/P的疾病基因。这种多阶段的方法，这还没有被应用到CL/P，是非常强大的，因为不需要有关的遗传或生物过程的先验知识。 待检验的假设：非综合征性CLIP是由一个或多个基因座的遗传变异引起的。 为了检验这一假设，将从多个临床中心招募具有多个受影响成员和母亲/父亲和受影响儿童三人组的CL/P家庭。这些家族将是初步评估候选基因的基础，以使用连锁和连锁不平衡的遗传工具来测试上述假设，以拒绝（排除）或提供支持（即连锁）假设的证据。还将进行10 cM全基因组筛选以发现其他基因座。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间隔的标记物进行进一步评价。它将通过多中心的项目，如这个，在世界范围内的合作已经建立，应用互补的遗传策略的组合，CL/P的疾病位点将被确定。最终，这将进一步了解正常和异常的颅面发育，从而可以开发和实施预防CL/P的治疗方法。