Molecular and cellular mechanisms causing cleft lip/palate

导致唇裂/腭裂的分子和细胞机制

基本信息

批准号：
10570890
负责人：
Timothy Chilton Cox
金额：
$ 52.3万
依托单位：
UNIVERSITY OF MISSOURI KANSAS CITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10570890
关键词：
Adherens Junction Adhesions Alveolus Behavior Biological Assay CDH1 gene Candidate Disease Gene Cell Adhesion Cell Culture Techniques Cell Nucleus Cell Surface Proteins Cell physiology Cell-Cell Adhesion Cellular Assay Chick Embryo Cleft Palate Cleft lip with or without cleft palate Clustered Regularly Interspaced Short Palindromic Repeats Complex Congenital Abnormality Cytoplasm Cytoskeleton Data Defect Development E-Cadherin Embryo Endocytosis Epithelial Cells Epithelium Event Face Family Genes Genetic Genetic Transcription Genomic Segment Growth Factor Human Incidence Individual International Link Lip structure Live Birth Microtubules Modeling Molecular Morphology Mutation NME1 gene Nature Nonmetastatic PVRL1 Pathogenicity Pathway interactions Patients Penetrance Phosphoric Monoester Hydrolases Play Point Mutation Predisposition Process Protein Phosphatase 2A Regulatory Subunit PR53 Proteins Quality of life Regulation Research Role Severities Signal Pathway Syndrome System Therapeutic Intervention Tissues Variant Work beta catenin candidate identification cell behavior cleft lip and palate cohort exome sequencing gene function genome wide association study improved innovation insight lip morphogenesis man mouse model novel oral cavity epithelium prevent protein phosphatase 6 success transcription factor transcription regulatory network ubiquitin-protein ligase

项目摘要

Project Summary Cleft lip with or without cleft palate (CLP) is one of the most common birth defects in man with an incidence of between 1 in 700 and 1 in 1000 live births worldwide. Considerable progress has been made over the last few decades to determine the genes responsible for syndromic forms of CLP and genome-wide association studies have implicated many genomic regions (and candidate genes) in the genetic contribution to non-syndromic CLP. However, for a substantial fraction of cleft cases, the underlying genetic basis remains unknown. In addition, much of the focus on cleft gene functions has been on the few transcriptional regulators and growth factors that have been implicated, largely ignoring the many other causative genes. He we pursue new findings from two known CLP proteins, IRF6 and MID1, that suggest a convergence of function around the direct regulation of epithelial cell-cell adhesion during lip morphogenesis. The project investigates the newly discovered linkages that each of these proteins have with processes responsible for coordinating the dynamic behavior of intercellular adhesion complexes with the underlying changes in the cellular cytoskeleton that ultimately facilitate morphogenesis of the lip. In addition, we provide further support for the importance of components of this specific regulatory complex by investigating the direct functional impact of likely pathogenic variants recently discovered in a cohort of large multigenerational families with non-syndromic CLP. The project is highlighted not just by the unique insight into the molecular mechanisms underlying CLP that the research plan offers, but also the various novel and state-of-the-art approaches used to pursue the work aimed at understanding the causes of this common birth defect.

项目概要唇裂伴或不伴腭裂 (CLP) 是男性最常见的出生缺陷之一，发病率全球有七百分之一到千分之一的活产婴儿。过去几年已经取得了相当大的进展几十年来确定导致 CLP 综合征形式的基因和全基因组关联研究涉及许多基因组区域（和候选基因）对非综合征的遗传贡献中电。然而，对于很大一部分唇裂病例，其潜在的遗传基础仍然未知。在此外，对裂口基因功能的大部分关注都集中在少数转录调节因子和生长上所涉及的因素，很大程度上忽略了许多其他致病基因。他我们追求新的发现来自两个已知的 CLP 蛋白 IRF6 和 MID1，这表明围绕直接唇形态发生过程中上皮细胞-细胞粘附的调节。该项目研究了新发现了这些蛋白质中的每一个与负责协调动态的过程之间的联系细胞间粘附复合物的行为与细胞骨架的潜在变化最终促进唇部的形态发生。此外，我们还为以下方面的重要性提供进一步支持：通过研究可能的致病性的直接功能影响来确定这一特定调控复合体的组成部分最近在一群患有非综合征性 CLP 的大型多代家庭中发现了变异。这该项目的突出之处不仅在于对 CLP 分子机制的独特见解研究计划提供了，而且还提供了用于开展目标工作的各种新颖和最先进的方法了解这种常见出生缺陷的原因。