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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 根据NHANES的最新调查(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，这表明母亲肥胖(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是在胎儿和新生儿阶段完成的。我们的初步数据显示，MO导致胎儿全身炎症，Toll样受体(TLR4)表达增加。我们假设，MO在胎儿中诱导全身炎症，促进宿主来源抗原特异性胸腺细胞的存活，增加后代包括I型糖尿病在内的自身免疫性疾病的发生率。我们用非肥胖糖尿病(NOD)小鼠喂养对照组(CON)或肥胖饮食(OB)来研究MO对子代I型糖尿病发病率的影响。我们还利用TLR4基因敲除小鼠来研究TLR4在胎儿免疫系统发育中的作用。基于这项研究获得的数据，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，并制定应对自身免疫性疾病的具体策略。这项研究获得的知识将为干预措施提供目标，以确保免疫系统的适当发展，改善该国日益增多的肥胖孕妇的后代的生活质量。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.