Matrix Metalloproteinase Gene Variants and Cleft Lip and Palate

目前的提案寻求激活K99 R 00合同的ROO阶段（1 K99/ROO-DE 018954）。的PI 已经实现了K99阶段的职业目标和研究目标，并准备进入一个 在ROO阶段的独立位置。体制支持和环境有助于 Pi的成就。该建议的实验重点是MMP基因变异和唇裂， 无腭裂（CL/P）。CL/P是一种常见的先天性异常，由胚胎发育期间的缺陷引起。 发展CL/P的病因是多因素的，假设有多种遗传和环境因素 负责任MMP基因在胚胎发育过程中所需的组织重塑中起重要作用， 发展，并可能参与CL/P病因。研究假设基因的不平衡 由于DNA多态性引起的转录可能改变细胞外基质合成的速率， 在颅面发育过程中降解（从而组织重塑），因此易患口腔疾病。 裂缝计划用于ROD随访的实验是在本研究的K99阶段获得的结果。 奖简而言之，具体目标。是为了研究多态性的生物学效应， K99期CL/P在CL/P病因学中的潜在作用。特别强调的是 基因启动子中的多态性对于它们调节基因表达的能力是重要的。两个实验 将使用的方法。瞬时转染将用于实现依赖于等位基因的基因功能 活动电泳迁移率变动分析（EMSA）将用于验证蛋白质/DNA相互作用， 给定基因的上游调控区。了解疾病相关SNP的功能是一个。 为遗传关联研究提供了重要的补充和验证。在这项建议中，任何 相关的多态性是揭示功能可能提供重要的见解CL/P的病因， 以及未来长期研究的不同视角。该研究具有创新性， 研究领域。这与NIH使命对未来治疗可能性的倡议相一致。

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.