PREVENTION OF NEURAL TUBE DEFECTS BY IMMUNE STIMULATION

简介(由申请人提供)：特里·赫贝克博士获得了医学博士学位和博士学位，并开始从事研究工作。她是一位积极进取的科学家，希望将职业生涯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。这一奖项将为赫贝克博士提供加强和扩展研究技能的机会，方法是提供发育异常分子机制方面的培训，并使用人类疾病的动物模型。这项拟议的研究调查了母体免疫刺激预防丙戊酸(VA)导致出生缺陷的机制。维生素A是一种常用于治疗癫痫的药物，具有致畸性，在1%到2%的暴露胎儿中会导致神经管缺陷(NTD)，其发生率是普通人群的20倍。在研究人员认为这是一项改变范式的工作中，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著减少各种化学诱导的出生缺陷，包括VA诱导的NTDS。此外，研究人员还表明，在乌拉坦诱导的腭裂中，这种母体免疫刺激可以使几个选定的胎儿细胞周期/凋亡调控基因在致畸因素改变的情况下正常表达。现在，对VA诱导的NTDS中基因表达变化的更有针对性的检查是合乎逻辑的。具体地说，研究人员将测试假设：1)VA影响调节神经管发育的基因的表达，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；2)补充叶酸通过与细胞因子相关的机制保护NTDS，这可能在一定程度上类似于母体免疫刺激后产生的机制。这些研究有望显著提高研究人员对母亲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，因为确定涉及的机制将提高对这种疾病的理解，从而预防或治愈这种疾病。这项研究将在VPISU弗吉尼亚-马里兰州地区兽医学院的Steven Holladay博士和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.