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

 描述（由申请人提供）：唇裂和/或腭裂（CL/P）是最常见的面部出生缺陷。这种正常面部结构的破坏可能会导致呼吸、进食和言语发育等必要功能出现困难。 CL/P 的临床表现变化很大，表明该疾病可能是由遗传和环境因素复杂的相互作用引起的。目前人们对确定与遗传易感性相互作用从而影响 CL/P 临床表现的环境因素非常感兴趣，因为对这些因素的进一步了解可能会带来重要的新治疗和干预措施。母亲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。该项目将研究母亲饮食中的基因型和维生素 A 水平如何相互作用，从而影响中面部发育以及 CL/P 敏感性和严重程度。在该项目的第一个目标中，将使用能够精确控制维生素 A 生物利用度水平的小鼠模型来评估轻度和中度母亲维生素 A 缺乏 (VAD) 对面部表型的影响。使用可变形形态分析，表型差异将被量化，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通过饮食控制维生素 A 和/或 CL/P 敏感性的小鼠模型来研究轻度和中度母亲 VAD 以及母亲维生素 A 补充剂对 CL/P 严重程度和频率的影响。表型的严重性将使用可变形形态学方法进行量化。预计结果将显示与母体 VAD 程度相对应的唇裂严重程度和频率的增加以及与补充维生素 A 相关的保护作用。这项工作将进一步了解导致 CL/P 易感性和敏感性的潜在机制和环境调节剂，这将有助于确定最佳治疗和预防策略。

 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.