Mechanisms by Which IUGR Leads to Diabetes

项目总结 宫内生长受限(IUGR)是妊娠的常见并发症，与 2型糖尿病(T2D)的后期发展。我们已经研制出一种实验动物 子宫胎盘功能不全致胎儿宫内发育迟缓模型的建立 通过永久性地改变易感细胞，如？细胞，并导致T2D的发展 在成年后。我们的初步数据表明，IUGR导致 T2D在成年期的发展是通过胎儿胰岛中Th2反应的短暂激活来实现的 导致局部炎症。这与高水平的IL-4的产生有关 和IL-10在胎儿胰岛的表达。尽管这种免疫反应是短暂的，但它会导致永久性的 胰岛血管减少和胰岛素分泌受损。然而，目前还不知道是哪一种 免疫细胞或T细胞亚型有助于这些Th2细胞因子的产生。因为每一个 这些免疫细胞类型在免疫调节中具有特殊的作用，因此至关重要的是 确定T细胞亚群的表型分布。令人惊讶的是，阻止单曲的动作 Th2细胞因子IL-4可以永久性地恢复IUGR成年动物的血管和细胞功能。 这表明IL-4策划了一系列导致异常？细胞的事件。 IUGR动物的表型。表观遗传机制调节Th2细胞激活 胎儿和成人。Th2细胞因子基因在静息状态下高度保守和去甲基化 胎儿和新生儿的CD4+细胞。因此，额外的表观遗传机制必须是 IUGR细胞Th2效应器功能被夸大。这些发现使我们假设 IUGR诱导巨噬细胞和嗜酸性粒细胞等Th2型效应细胞的扩增 通过表观遗传机制发生，导致永久性的？细胞功能障碍。我们建议 以下目标：特定目标1：确定胎儿IUGR免疫细胞是否具有 与对照组不同，导致放大的Th2反应。具体目标2：定义 IUGR胎儿和新生儿免疫细胞的表观遗传格局。具体目标3：确定 IL4产生导致IUGR动物矿化细胞功能障碍的机制。 通过在活体模型中的综合分析，提出了项目的结果 将建立一个可靠的标准来推断其他类型的影响和行动模式 可能被确定为肥胖和相关潜在诱因的炎症过程 晚年的代谢性疾病。

PROJECT SUMMARY Intrauterine growth restriction (IUGR) is a common complication of pregnancy and is linked to the later development of type 2 diabetes (T2D). We have developed an experimental animal model of IUGR caused by uteroplacental insufficiency that affects the development of the fetus by permanently altering susceptible cells, such as ß-cells, and leads to the development of T2D in adulthood. Our preliminary data suggest that the mechanism by which IUGR leads to the development of T2D in adulthood is via a transient activation of the Th2 response in fetal islets resulting in localized inflammation. This is associated with the production of high levels of IL-4 and IL-10 in fetal islets. Although this immune response is short- lived, it results in a permanent reduction in islet vascularity and impaired insulin secretion. However, it is not known which immune cells or T cell subtypes contribute to the production of these Th2 cytokines. As each of these immune cell types have a particular role in immune regulation, it is critically important to determine the phenotypic profile of T cell subsets. Surprisingly, blocking the action of a single Th2 cytokine, IL-4, restores vascularity and ß-cell function permanently in IUGR adult animals. This suggests that IL-4 orchestrates a cascade of events leading to the abnormal ß-cell phenotype in the IUGR animal. Epigenetic mechanisms regulate Th2 cell activation both in the fetus and adult. The Th2 cytokine locus is highly conserved and demethylated in resting normal fetal and neonatal CD4+ cells. Thus, additional epigenetic mechanisms must underlie the exaggerated Th2 effector function in IUGR cells. These findings lead us to hypothesize that IUGR induced expansion of Th2-type effector cells including macrophages and eosinophils occurs via epigenetic mechanisms resulting in permanent ß-cell dysfunction. We propose the following aims: Specific Aim 1: To determine whether fetal IUGR immune cells are functionally distinct from controls resulting in an amplified Th2 response. Specific Aim 2: To define the epigenetic landscape in IUGR fetal and neonatal immune cells. Specific Aim 3: Determine the mechanisms by which IL4 production causes ß-cell dysfunction in IUGR animals. Through the comprehensive analyses in the in vivo model, the results of the proposed project will build a solid standard for extrapolation of effects and mode of action to other types of inflammatory processes that may be identified as potential inducers of obesity and related metabolic diseases later in life.