PREVENTION OF NEURAL TUBE DEFECTS BY IMMUNE STIMULATION

简介（由申请人提供）：Terry Hrubec博士获得了D.V.M.和博士学位，正在从事研究工作。她是一位非常积极的科学家，希望从水生物种的临床病理学和免疫学转向哺乳动物细胞和分子免疫学的研究。该奖项将为Hrubec博士提供机会，通过提供发育异常分子机制方面的培训和使用人类疾病的动物模型，加强和扩大研究技能。本研究旨在探讨母体免疫刺激预防丙戊酸（VA）所致出生缺陷的机制。VA是一种通常用于治疗癫痫的药物，它具有致畸性，在1%至2%的暴露胎儿中诱发神经管缺陷（NTDs），其发生率是普通人群的20倍。研究人员认为这是一项改变范式的工作，来自研究人员实验室的数据确凿地证明，啮齿类动物母体免疫系统的非特异性激活可以显著减少各种化学物质诱导的出生缺陷，包括VA诱导的NTDs。此外，研究人员已经表明，这种母体免疫刺激使致畸原改变的一些胎儿细胞周期/凋亡调节基因在聚氨酯诱导的腭裂中表达正常化。现在，对VA诱导的NTDs基因表达改变进行更集中的检查是合乎逻辑的。具体而言，研究人员将验证以下假设：1)VA影响调节神经管发育的基因表达，母体免疫刺激通过激活免疫细胞分泌的调节蛋白（细胞因子）使基因表达正常化；2)补充叶酸可通过细胞因子相关机制预防NTDs，这可能部分类似于母体免疫刺激后产生的机制。这些研究有望显著增加研究者对母体免疫调节减少这种特定出生缺陷的遗传机制的理解。显然，这项研究对人类健康很重要，因为确定所涉及的机制将提高对这种疾病的理解，从而导致预防或治疗。本研究将在dr。维吉尼亚-马里兰地区兽医学院的Steven Holladay和Ansar Ahmed，并将为Hrubec博士提供优秀的培训和职业发展。

DESCRIPTION (provided by applicant): Dr. Terry Hrubec received the D.V.M. and Ph.D. degrees and is embarking on a research career. She is a highly motivated scientist who wishes to make a career shift from clinical pathology and immunology of aquatic species to research in mammalian cellular and molecular immunology. This award would offer Dr. Hrubec an opportunity to strengthen and expand research skills by affording training in molecular mechanisms of developmental abnormalities and using animal models of human disease. The proposed research investigates the mechanism by which maternal immune stimulation prevents valproic acid (VA) induced birth defects. VA, a drug commonly used to treat epilepsy, is teratogenic and induces neural tube defects (NTDs) in one to two percent of exposed fetuses at a rate 20 times higher than in the general population. In what the investigators feel is paradigm-changing work, data from the investigators' laboratory have conclusively demonstrated that non-specific activation of the maternal immune system in rodents can dramatically reduce a variety of chemical-induced birth defects, including VA induced NTDs. Additionally, the investigators have shown that such maternal immune stimulation normalizes teratogen-altered expression of a few selected fetal cell-cycle/apoptotic regulatory genes in urethane-induced cleft palate. A more focused examination of altered gene expression in VA induced NTDs is now logical. Specifically, the investigators will test the hypotheses that: 1) VA affects the expression of genes regulating neural tube development, and that maternal immune stimulation normalizes gene expression through regulatory proteins (cytokines) secreted by activated immune cells; and 2) folic acid supplementation protects against NTDs by cytokine-related mechanisms which may in part be similar to that resulting after maternal immune stimulation. These studies are expected to significantly increase the investigators' understanding of genetic mechanisms by which maternal immune modulation reduces this specific birth defect. Clearly, this research is of importance to human health, as determining the mechanisms involved will improve the understanding of this disorder leading to a prevention or cure. This research will be conducted under the guidance of Drs. Steven Holladay and Ansar Ahmed of the Virginia-Maryland Regional College of Veterinary Medicine at the VPISU, and will offer excellent training and career development for Dr. Hrubec.