MATERNAL OBESITY AND DEVELOPMENT OF TYPE 1 DIABETES IN NOD MICE OFFSPRING

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 根据最新的国家健康和营养状况调查（1999-2002年），29%的育龄妇女（20-39岁）肥胖。与此同时，包括I型糖尿病在内的自身免疫性疾病也在增加，这表明母体肥胖（MO）与免疫系统发育改变之间可能存在联系。免疫系统发育的主要组成部分在胎儿和新生儿阶段完成。我们的初步数据表明，MO导致胎儿全身炎症和Toll样受体（TLR）4的表达升高。我们假设MO诱导胎儿全身性炎症，这促进了对宿主衍生抗原特异性的胸腺细胞的存活，增加了后代自身免疫性疾病包括I型糖尿病的发病率。我们正在使用良好建立的非肥胖糖尿病（NOD）小鼠喂养对照（Con）或致肥胖（OB）饮食，以研究MO对后代I型糖尿病发病率的影响。我们还利用TLR 4基因敲除小鼠来研究TLR 4在胎儿免疫系统发育中的作用。 基于本研究获得的数据，PI将进一步探索与胎儿免疫系统发育和免疫耐受相关的机制，并制定科普自身免疫性疾病的具体策略。这项研究中获得的知识将为干预措施提供目标，以确保免疫系统的正常发育，提高该国越来越多肥胖孕妇后代的生活质量。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. According to the latest NHANES survey (1999-2002), 29% of women at childbearing age (20-39 years old) are obese. At the same time, autoimmune diseases including Type I diabetes are also increasing, indicating a likely link between maternal obesity (MO) and altered immune system development. Major components of immune system development are accomplished during the fetal and neonatal stages. Our preliminary data show that MO led to systemic inflammation in fetuses and the expression of toll like receptor (TLR) 4 was elevated. We hypothesized that MO induces systemic inflammation in fetus, which promotes survival of thymocytes specific to host-derived antigens, increasing the incidence of autoimmune diseases including type I diabetes in offspring. We are using well-established non-obese diabetic (NOD) mice fed control (Con) or obesogenic (OB) diet to study the effect of MO on the incidences of offspring type I diabetes. We also utilize TLR4 knockout mice to study the role of TLR4 in the fetal immune system development. Based on the data obtained from this study, the PI will further explore mechanisms associated with the fetal immune system development and immune tolerance, and develop specific strategies to cope with autoimmune diseases. Knowledge obtained in this study will provide targets for interventions to ensure the proper development of the immune system, improving the quality of life for the offspring of the increasing number of obese pregnant women in this country.