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PREVENTION OF NEURAL TUBE DEFECTS BY IMMUNE STIMULATION

通过免疫刺激预防神经管缺陷

基本信息

批准号：
7269446
负责人：
THERESA C HRUBEC
金额：
$ 13.5万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7269446
关键词：
Address Affect Animal Model Animals Apoptotic Award Bioclon brand of benzyl benzoate Biological Response Modifiers Birth Cell Cycle Cells Chemicals Cleft Palate Clinical Pathology Closure Colony-Stimulating Factors Congenital Abnormality Cyclophosphamide Cytokine Gene Data Defect Development Disease Doctor of Philosophy Doctor of Veterinary Medicine Drug or Chemical End Point Enzyme-Linked Immunosorbent Assay Epilepsy Evaluation Family Fetus Folate Folic Acid Future Gene Expression General Population Genes Genetic Goals Granulocyte-Macrophage Colony-Stimulating Factor Growth Factor Health Human Immune Immune system Immunology Inbred DBA Mice Inbred ICR Mice Incidence Injection of therapeutic agent Interleukins Laboratories Laboratory Animals Lesion Leukocytes Maryland Mediating Mediator of activation protein Messenger RNA Molecular Molecular Immunology Mothers Mouse Strains Mus Mutation Neural Tube Closure Neural Tube Defects Neural Tube Development Numbers Palate Patient currently pregnant Pharmaceutical Preparations Placenta Predisposition Prevention Proteins Rate Regulator Genes Reporting Research Research Personnel Resistance Rodent Role Role playing therapy Scientist Severities Spleen Supplementation TP53 gene Teratogens Testing Time Tissues Training Transcript Treatment Efficacy Tube Urethane Valproic Acid Veterinary Medicine Virginia Work career chemical reduction college craniofacial cytokine fetal fetus cell genetic regulatory protein human disease immunoregulation improved peripheral blood prevent programs receptor relating to nervous system research study skills

项目摘要

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.

描述（由申请人提供）：Terry Hrubec 博士获得了 D.V.M.和博士学位。学位并正在开始研究生涯。她是一位积极主动的科学家，希望将职业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展研究技能。拟议的研究调查了母体免疫刺激预防丙戊酸（VA）引起的出生缺陷的机制。 VA 是一种常用来治疗癫痫的药物，具有致畸性，并会导致 1% 到 2% 的胎儿出现神经管缺陷 (NTD)，其发生率比普通人群高 20 倍。在研究人员认为是范式改变的工作中，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引起的出生缺陷，包括 VA 引起的 NTD。此外，研究人员还表明，这种母体免疫刺激可以使尿烷诱发的腭裂中一些选定的胎儿细胞周期/凋亡调节基因的致畸改变表达正常化。现在，对 VA 诱导的 NTD 中基因表达的改变进行更集中的检查是合乎逻辑的。具体来说，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，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) 补充叶酸可通过细胞因子相关机制预防 NTD，这可能部分类似于母体免疫刺激后产生的机制。这些研究预计将显着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非常重要，因为确定所涉及的机制将提高对这种疾病的了解，从而预防或治愈这种疾病。这项研究将在博士的指导下进行。 VPISU 弗吉尼亚-马里兰地区兽医学院的 Steven Holladay 和 Ansar Ahmed 将为 Hrubec 博士提供出色的培训和职业发展。