Interaction of Genotype and Dietary Vitamin A in Cleft Lip and/or Palate

 描述(申请人提供)：唇腭裂(CL/P)是最常见的面部出生缺陷。这种正常面部结构的破坏会导致呼吸、进食和语言发育等必要功能的困难。CL/P的临床表现具有很高的变异性，表明这种疾病可能是由遗传和环境因素的复杂相互作用引起的。目前，人们对识别与遗传易感性相互作用的环境因素影响CL/P的临床表现非常感兴趣，因为对这些因素的进一步了解可能导致重要的新的治疗和干预措施。孕妇营养既是已知的对颅面发育的影响，也是未来干预的理想目标。该项目将调查孕妇饮食中的基因和维生素A水平如何相互作用，影响面部中部发育和CL/P的易感性和严重性。在该项目的第一个目标中，将使用一个能够精确控制生物可用维生素A水平的小鼠模型来评估轻度和中度母亲维生素A缺乏症(VAD)对面部表型的影响。利用可变形形态分析，表型的差异将被量化，并有望揭示与母亲VAD程度相对应的面部形态变化的分级程度。该项目的第二个目标将使用允许饮食控制维生素A和/或CL/P敏感性的小鼠模型来调查轻度和中度母亲VAD和母亲补充维生素A对CL/P严重程度和频率的影响。表型的严重程度将使用可变形的形态学方法进行量化。预计结果将显示，与母亲VAD的程度相对应的裂隙严重程度和频率增加，以及补充维生素A相关的保护作用。这项工作将促进对CL/P易感性和敏感性的潜在机制和环境调节剂的理解，这将有助于确定最佳的治疗和预防策略。

 DESCRIPTION (provided by applicant): Clefting of the lip and/or palate (CL/P) is the most common facial birth defect. This disruption of normal facial structure can lead to difficulties wit necessary functions such as breathing, feeding, and speech development. Clinical manifestations of CL/P are highly variable, indicating that the disorder is likely caused by a complex interaction of genetic and environmental factors. There is currently great interest in identifying the environmental factors that interact with genetic susceptibility to effect clinical presentation of CL/P, as further understanding of these factors could lead to important new treatments and interventions. Maternal nutrition is both a known influence on craniofacial development and an ideal target for future interventions. This project will investigate how genotype and vitamin A levels in the maternal diet interact to influence midfacial development and CL/P susceptibility and severity. In the first aim of this project, a mouse model allowing precise control over bioavailable levels of vitamin A will be used to assess the impact of mild and moderate maternal vitamin A deficiency (VAD) on facial phenotype. Using deformable morphology analysis, difference in phenotypes will be quantified and are expected to reveal a graded degree of change in facial morphology corresponding to the degree of maternal VAD. The second aim of this project will use mouse models allowing dietary control of vitamin A and/or CL/P sensitivity to investigate the impact of mild and moderate maternal VAD and maternal vitamin A supplementation on CL/P severity and frequency. Severity of phenotypes will be quantified using deformable morphology methods. The results are expected to show an increase in cleft severity and frequency corresponding to the degree of maternal VAD and a protective effect associated with vitamin A supplementation. This work will further the understanding of the underlying mechanisms and environmental modulators contributing to CL/P susceptibility and sensitivity which will help identify optimal treatment and preventative strategies.