Matrix Metalloproteinase Gene Variants and Cleft Lip and Palate

基质金属蛋白酶基因变异与唇腭裂

• 批准号: 8068760
• 负责人: Ariadne M Letra
• 金额: $ 2.76万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-07-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8068760
• 关键词: Achievement; Alleles; Animal Model; Award; Basement membrane; Biological; Birth; Cleaved cell; Cleft Palate; Cleft lip with or without cleft palate; DNA; DNA-Protein Interaction; Data; Defect; Development; Disease; Economic Burden; Electrophoretic Mobility Shift Assay; Embryonic Development; Environment; Environmental Risk Factor; Equilibrium; Etiology; Extracellular Matrix; Family; Future; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Transcription; Genetic Variation; Goals; Incidence; Inhibition of Matrix Metalloproteinases Pathway; Intervention; Investigation; Matrix Metalloproteinases; Measures; Medical; Metalloproteinase Gene; Mission; Morphogenesis; Nucleic Acid Regulatory Sequences; Palate; Peptide Hydrolases; Phase; Physiological; Play; Positioning Attribute; Protein Binding; Research; Role; Societies; Solid; Testing; Tissue Inhibitor of Metalloproteinases; Tissues; Transfection; Transgenic Organisms; United States; United States National Institutes of Health; Validation; Variant; base; career; cleft lip and palate; craniofacial; follow-up; genetic association; human MMP14 protein; improved; innovation; insight; knockout animal; oral cleft; palatal fusion; palatal shelves; promoter; research study

The current proposal seeks activation of the ROO phase of a K99R00 award (1K99/ROO-DE018954). The PI has fulfilled the career goals and research aims planned for the K99 phase and is ready to move to an independent position in the ROO phase. The institutional support and environment have been instrumental for the Pi's achievements. The experimental focus of this proposal is on MMP gene variants and cleft lip with or without cleft palate (CL/P). CL/P is a common congenital anomaly that results from defects during embryonic development. The etiology of CL/P is multifactorial with multiple genetic and environmental factors assumed to be responsible. MMP genes play a significant role in the tissue remodeling required during embryonic development and may be involved in CL/P etiology. The study hypothesis is that imbalances in gene transcription due to DNA polymorphisms may alter the rates of extracellular matrix synthesis and degradation (and thus tissue remodeling) during craniofacial development and hence predispose to oral clefts. The experiments planned for the ROD follow-up on results obtained during the K99 phase of this award. Briefly, the Specific Aim. is to investigate the biological effects of the polymorphisms associated with CL/P in the K99 phase with regards to a potential role in CL/P etiology. Special emphasis wil be ¿iven to polymorphisms in the gene promoters for their ability to regulate gene expression. Two experimental approaches will be used. Transient transfection will be used to afsess allele-dependent gene functional activity. Electrophoretic mobility shift assays (EMSA) will be used to verify protein/DNA interactions vwthin a given gene's upstream regulatory region. Understanding the functionality of disease-associated SNPs is an . important complementation and validation for genetic association studies. In the context of this proposal, any associated polymorphism that is revealed functional may provide important insights into the etiology of CL/P, and different perspectives for future research in the long-term. The proposed study constitutes ari innovative field of research.^nd confonns to.the initiatives of the NIH mission for future treatment possibilities.

当前的提案寻求激活K99R00奖的ROO阶段（1K99/ROO-DE018954）。 pi 已经实现了K99阶段计划的职业目标和研究目标 在ROO阶段的独立位置。机构支持和环境对 PI的成就。该提案的实验重点是带有OR或 没有left裂（Cl/p）。 Cl/p是一种常见的先天性异常，是由于胚胎期间缺陷引起的 发展。 Cl/p的病因是多因素，假定多个遗传和环境因素 负责。 MMP基因在胚胎中所需的组织重塑中起重要作用 开发并可能参与CL/P病因。研究假设是基因失衡 由于DNA多态性引起的转录可能会改变细胞外基质合成的速率和 在颅面发育过程中降解（因此是组织重塑），因此倾向于口服 裂口。计划在此期间获得的结果的杆随访的实验 奖。简而言之，具体目标。是为了研究与 在K99阶段的Cl/P关于CL/P病因的潜在作用。特别强调 基因启动子中的多态性调节基因表达的能力。两个实验 将使用方法。瞬态翻译将用于AFSESS等位基因依赖性基因功能 活动。电泳移动性转移测定（EMSA）将用于验证蛋白质/DNA相互作用vwthin a 考虑到基因的上游监管区域。了解与疾病相关的SNP的功能是一个。 遗传关联研究的重要完成和验证。在此提案的背景下，任何 揭示功能的相关多态性可以为Cl/p的病因提供重要的见解， 从长远来看，对未来研究的不同观点。拟议的研究构成了ARI创新 研究领域。