Transcriptional Coactivators and Pregnancy Outcomes

描述（由申请人提供）：两个主要的医疗保健问题不可避免地交织在一起：妇女的健康和未出生孩子的产前发育。母体叶酸状况对中枢神经系统（CNS）的发育以及某些中枢神经系统发育障碍（神经管缺陷，NTDs）的发生率和复发有深远影响。虽然NTDs是人类最常见的畸形之一，但叶酸对这些畸形的改善作用或其在中枢神经系统正常形态发生中的作用的机制尚不清楚。现有的数据表明叶酸状态和发育途径之间的相互作用是由特定的转录调控因子控制的。本文探讨了这种相互作用的本质，并由五个假设驱动的特定目标组成，这些目标联系在一起，以呈现特定翻译共激活因子介导信号转导并促进发育中的中枢神经系统发展的分子机制的凝聚力。所提出的具体目标需要验证的总体假设是，哺乳动物胚胎中正常的中枢神经系统发育需要叶酸介导的转录复合体的激活，而转录复合体在功能上依赖于特定转录共激活因子的适当表达和整合。具体来说，我们提出，不仅Folbp和转录共激活因子（如CBP、p300、Cited2、Cart1和AP-2）的适当表达是中枢神经系统形成的必要条件，而且这些分子整合到一个功能调控中对正常中枢神经系统形态发生至关重要。对旨在揭示诸如北侧缺陷等先天性异常原因的研究进行投资，为满足公共卫生服务部门关于生物医学必须为社会带来好处的要求提供了极好的机会。当前应用程序中提出的实验旨在鉴定与NT缺陷易感性相关的基因、遗传变异和分子途径，并了解与此类疾病相关的信号传导机制。旁白：在美国，每三分钟就有一个婴儿出生时有先天缺陷！虽然神经管缺陷（NTDs）是人类最常见的畸形之一，但叶酸对这些畸形的改善作用或其在神经管正常发育中的作用的机制尚不清楚。当前申请中提出的研究应能更好地了解影响孕妇营养/健康状况的产前因素，以及它们对发育中的胎儿健康的影响，特别是与被忽视的热带病有关的影响。

DESCRIPTION (provided by applicant): Two major medical health care issues are inexorably intertwined: a woman's health, and prenatal development of her unborn child. Maternal folate status is one condition that has a profound influence on development of the central nervous system (CNS), and the incidence and recurrence of certain developmental disorders of the CNS (neural tube defects, NTDs). While NTDs are amongst the most common human malformations, the mechanisms by which folate exerts its ameliorative effect on these malformations, or its role in normal morphogenesis of the CNS, is not well understood. Extant data argue for interactions between folate status and developmental pathways controlled by specific transcriptional regulators. This proposal explores the nature of such interactions and consists of five, hypothesis-driven, specific aims linked together in order to present a cohesive picture of the molecular mechanisms by which specific translational coactivators mediate signal transduction in, and contribute to development of, the developing CNS. The overall hypothesis to be tested by the proposed specific aims is that normal CNS development in the mammalian embryo requires folate-mediated activation of a transcriptional complex, functionally dependent on proper expression and integration of specific transcriptional coactivators. Specifically, we propose that not only is proper expression of Folbp and transcriptional coactivators such as CBP, p300, Cited2, Cart1, and AP-2 requisite for CNS formation, but the integration of these molecules into a functional regulon is critical to normal CNS morphogenesis. Investments in research designed to reveal the causes of congenital anomalies such as NT defects provide excellent opportunities to meet Public Health Service requirements that biomedical science must pay social dividends. Experiments proposed in the current application seek to identify genes, genetic variations and molecular pathways associated with susceptibility to NT defects and to understand signaling mechanisms associated with such disorders.NARRATIVE: In the United States, every three minutes a baby is born with a birth defect! While neural tube defects (NTDs) are amongst the most common human malformations, the mechanisms by which folic acid exerts its ameliorative effect on these malformations, or its role in normal development of the neural tube, is not well understood. Studies proposed in the current application should provide a better understanding of prenatal factors influencing the nutritional/health status of pregnant women, and their impact on the health of the developing fetus, particularly as it relates to NTDs.