Maternal Hyperinsulinemia and Fetal Programming

描述(由申请人提供)：胎儿/新生儿的侮辱可能会导致 成人疾病(肥胖症、糖尿病等)但人们对此知之甚少 涉及的机制。我们已经证明了新生的大鼠 在哺乳期用高碳水化合物(HC)奶粉喂养 立即发生高胰岛素血症，这种情况会持续到成年，并 伴随着肥胖。这项建议是基于我们观察到的HC 雌性大鼠自发传递母性特征(慢性高胰岛素血症 和成人型肥胖)传给后代，这是由于胎儿经历了 高胰岛素血症/肥胖HG妊娠。为了阐明涉及到的机制 本文提出了母胎移植表型的三个具体目标： (一)调查母亲环境因素(S) 对胎儿B细胞编程，使其在断奶后出现高胰岛素血症。它是 假设荷尔蒙和代谢适应与这种 妊娠是导致子代高胰岛素血症的主要原因。 (2)探讨其生化和分子机制。 慢性高胰岛素血症--一种成人起病的HG子代肥胖 女性。假设是HG女性的宫内环境 子代胰岛的程序分子和生化变化 促进断奶时高胰岛素血症的发生及其持续到 成人期。(三)调查母体高胰岛素血症对胎儿的影响 和新生儿胰腺个体发育受血浆中胰岛素水平的影响 特定的增长因素(IGF、FGFs等)和转录因子。我们的 假说是宫内环境改变了胰腺细胞 子代发育对特异体水平变化的反应 生长因子和转录因子。实验程序包括： 人工饲养新生大鼠、胚胎移植、胰岛素 分离的胰岛分泌的放射免疫测定，半定量RT-PCR测定， 免疫组织化学和原位杂交。

DESCRIPTION (provided by applicant): Fetal/neonatal insults can lead to adult-onset diseases (obesity, diabetes, etc.) but little is known about the mechanisms involved. We have demonstrated that newborn rats artificially reared on a high carbohydrate (HC) milk formula during their suckling period immediately develop hyperinsulinemia, which persists into adulthood and is accompanied by obesity. This proposal is based on our observation that HC female rats spontaneously transmit maternal traits (chronic hyperinsulinemia and adult-onset obesity) to the progeny due to the fetal experience of a hyperinsulinemic/obese HG pregnancy. To elucidate the mechanisms involved in this maternal-fetal transfer of phenotype three specific aims are proposed: (1) Investigate the maternal environmental factor(s) responsible for programming fetal B cells to develop hyperinsulinemia after weaning. It is hypothesized that hormonal and metabolic adaptations associate with such a pregnancy are responsible for programming of hyperinsulinemia in the progeny. (2) Investigate the biochemical and molecular mechanisms responsible for chronic hyperinsulinemia an adult-onset obesity in the progeny born to HG females. The hypothesis is that the intrauterine environment of the HG female programs molecular and biochemical changes in islets of the progeny facilitating the onset of hyperinsulinemia on weaning and its persistence into adulthood. (iii) Investigate the effects of maternal hyperinsulinemia on fetal and neonatal pancreatic ontogeny as influenced by alterations in the levels of specific growth factors (IGFs, FGFs, etc.) and transcription factors. Our hypothesis is that the H( intrauterine environment alters pancreatic cellular development in the progeny in response to the change in levels of specific growth factors and transcription factors. Experimental procedures include: artificial rearing of newborn rats, reciprocal embryo transfer, insulin secretion by isolated islets radioimmunoassays, semiquantitative RT-PCR assay, immunohistochemistry and in situ hybridization.