Cleft Lip Genetics: A Multicenter International Consortium

唇裂遗传学：多中心国际联盟

• 批准号: 6788169
• 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/6788169
• 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饮异常的原因，这将为制定策略和疗法提供基础，以防止这种常见的先天性缺陷。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，以与新的发现和技术保持同步，以便在有必要的情况下可以快速整合到该项目中； 3）扩大我在人类遗传学以及分子和发育生物学方面的专业知识，使我能够发展一系列长期的技能，因为我的职业从疾病基因鉴定和分子表征发展到对动物模型的发展和研究，再到最终的预防疗法的发展和实施。 带有或没有裂口的唇唇（Cl/p）是常见的先天缺陷。先前的研究表明，Cl/P是由遗传因素和环境因素组合引起的复杂特征。这种复杂性的研究有限，因此仅在一个独特的家庭中发现了疾病突变。所有疾病基因座也不太可能被发现。该项目的总体目的是通过将新的多阶段链接和连锁不平衡（LD）策略应用于受影响的相对对和扩展的谱系中，以识别非蛋白质CL/P的疾病基因。这种多阶段方法尚未应用于Cl/P，非常有力，因为不需要关于涉及的遗传或生物过程的先验知识。 要测试的假设：非元素夹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，将从各种临床中心招募CL/P家族，具有多个受影响的成员，母亲/父亲和受影响的子三群岛。这些家族将是最初评估候选基因的基础，该基因使用链接和连锁的遗传工具不平衡（排除）或提供支持（即链接）的遗传工具（即链接）。还将进行10厘米全基因组屏幕以找到其他位点。通过使用更密集的分布标记，将通过多点，多核和TDT/关联分析的组合进一步评估阳性基因座。通过多个中心的项目，已经建立了全球合作以应用免费的遗传策略的组合，可以确定疾病基因座的CL/p WILT。最终，这将进一步了解正常和异常的颅面发展，从而可以开发和实施预防CL/P的疗法。