PREVENTION OF NEURAL TUBE DEFECTS BY IMMUNE STIMULATION

描述（由申请人提供）：Terry Hrubec博士收到了D.V.M.和博士学位，并开始了研究生涯。 她是一位积极进取的科学家，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博士提供一个机会，通过提供发育异常分子机制的培训和使用人类疾病的动物模型来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）诱导的出生缺陷的机制。 VA是一种常用于治疗癫痫的药物，具有致畸性，在1%至2%的暴露胎儿中诱导神经管缺陷（NTD），其发生率比一般人群高20倍。 在研究人员认为是改变范式的工作中，来自研究人员实验室的数据最终证明，啮齿动物母体免疫系统的非特异性激活可以显着减少各种化学诱导的出生缺陷，包括VA诱导的NTD。 此外，研究人员已经表明，这种母体免疫刺激使胎儿诱导的腭裂中一些选定的胎儿细胞周期/凋亡调控基因的致畸原改变表达正常化。 现在，对VA诱导的NTD中基因表达改变进行更集中的检查是合乎逻辑的。 具体而言，研究人员将测试以下假设：1）VA影响调节神经管发育的基因表达，并且母体免疫刺激通过激活的免疫细胞分泌的调节蛋白（细胞因子）使基因表达正常化;和2）叶酸补充剂通过精氨酸相关机制保护NTD，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人员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具有重要意义，因为确定所涉及的机制将提高对这种疾病的理解，从而预防或治愈。 这项研究将在VPISU马里兰州兽医区域学院的Steven Holladay和Ansar Ahmed博士的指导下进行，并将为Hrubec博士提供出色的培训和职业发展。

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.