Transcriptional Coactivators and Pregnancy Outcomes

描述（由申请人提供）：两个主要的医疗保健问题是无情地交织在一起：一个女人的健康，和她未出生的孩子的产前发育。母体叶酸状态是对中枢神经系统（CNS）的发育以及某些CNS发育障碍（神经管缺陷，NTD）的发生和复发具有深远影响的一种状况。虽然NTD是最常见的人类畸形之一，但叶酸对这些畸形发挥其改善作用的机制或其在CNS正常形态发生中的作用尚不清楚。现有的数据认为叶酸状态和发育途径之间的相互作用由特定的转录调控。该提案探讨了这种相互作用的性质，并由五个假设驱动的具体目标联系在一起，以提出一个有凝聚力的图片的分子机制，特定的翻译辅激活因子介导的信号转导，并有助于发展，发展中的中枢神经系统。拟通过提出的特定目的进行检验的总体假设是，哺乳动物胚胎中正常的CNS发育需要叶酸介导的转录复合物激活，其功能依赖于特定转录辅激活因子的正确表达和整合。具体来说，我们提出，不仅是适当的表达Folbp和转录辅激活因子，如CBP，p300，Cited 2，Cart 1，和AP-2必需的中枢神经系统的形成，但这些分子整合成一个功能调节子是至关重要的正常中枢神经系统的形态发生。对旨在揭示先天性异常（如NT缺陷）原因的研究的投资，为满足公共卫生服务的要求提供了极好的机会，即生物医学科学必须支付社会红利。本申请中提出的实验试图鉴定与NT缺陷易感性相关的基因、遗传变异和分子途径，并理解与这种疾病相关的信号传导机制。虽然神经管缺陷（NTD）是最常见的人类畸形之一，叶酸对这些畸形发挥其改善作用的机制，或其在神经管正常发育中的作用，还不清楚。本申请中提出的研究应更好地了解影响孕妇营养/健康状况的产前因素及其对发育中胎儿健康的影响，特别是与NTD相关的影响。

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.