REGULATION OF INTESTINAL BILE ACID BINDING PROTEIN

作为儿科胃肠病学的三年级研究员，申请人是 对研究肠道基因调控和开发 获得学术医学研究生涯所需的技能。 该提案的重点是肠道胆汁酸结合蛋白 （IBABP），一种被认为与胆汁酸有关的细胞溶质蛋白 (BA)肠肝循环（EHC）的吸收成分。 该系统维持BAP池，因此对脂质代谢至关重要。 消化和吸收。 IBABP mRNA出现在啮齿类动物中， 出生后第三周，与其他发育相一致的时间 EHC的部分，如回肠中的顶端转运蛋白（ASBT） 和肝BA合成。 这5年的奖励将提供丰富的 通过调查了解申请人的研究职业发展 IBABP是一种回肠标记物， EHC和肠道发育。 最初，生理学研究 将确定管腔BA和糖皮质激素（GC）在 乳鼠中IBABP和ASBT mRNA水平。 的可能性 IBABP和ASBT表达的起始由一种内在的 通过皮下移植胎鼠回肠来检查定时机制。 进入免疫缺陷小鼠。 在这个模型中， 管腔因素和正常的激素变化，发生在 发育大鼠 转录变化对细胞凋亡的贡献 正常发育期间IBABP mRNA稳态水平升高 用BA和GC诱导将通过核运行进行评估 测定。 随后，将进一步研究其内在机制。 在细胞水平上定义为内胚层/间充质分离 和重新联系。 在博士的实验室学习这项技术。 米歇尔·凯丁格代表了一个宝贵的机会， 这是一项在美国没有的技能。 最后，老鼠 IBABP基因将被分离和表征，以便顺式作用 介导个体基因调控的元件可以通过 体外转染和体内转基因小鼠研究。 博士 苏珊·亨宁的实验室，其主要重点是肠道 发展，是一个很好的环境，在其中发展， 提议 因为人类婴儿对BA的吸收也不成熟 如在乳鼠中，本项目可提供临床应用， 管理新生儿，尤其是早产儿。

A third-year fellow in pediatric gastroenterology, the applicant is interested in investigating intestinal gene regulation and developing the skills needed to attain a research career in academic medicine. The focus of the proposal is the intestinal bile acid binding protein (IBABP), a cytosolic protein believed to be involved in the bile acid (BA) absorption component of the enterohepatic circulation(EHC). This system maintain the BAP pool and thus is essential to lipid digestion and absorption. IBABP mRNA appears in rodents during the third postnatal week, a time coincident with the development of other parts of the EHC such as the apical transporter (ASBT) in the ileum and hepatic BA synthesis. This 5-yr award will provide enrichment of the applicant~s research career development through investigating the regulation of IBABP, an ileal marker which may provide insight into EHC and intestinal development. Initially, physiologic studies will determine the roles of luminal BA and gluco-corticoids (GC) on IBABP and ASBT mRNA levels in suckling rats. The possibility that the onset of IBABP and ASBT expression is controlled by an intrinsic timing mechanism will be examined by grafting fetal rat ileum s.c. into immune-deficient mice. In this model there is absence of luminal factors and the normal hormonal changes that occur in the developing rat. The contribution of transcriptional changes to the increased steady-state levels of IBABP mRNA during normal development and with BA and GC induction will be assessed by nuclear run-on assays. Subsequently, the intrinsic mechanism will be further defined at the cellular level with endoderm/mesenchyme dissociation and reassociations. Learning this technique in the laboratory of Dr. Michele Kedinger represents an invaluable opportunity to become adept at a skill which is not done in the United States. Finally, the rat IBABP gene will be isolated and characterized so that the cis-acting elements which mediate onto-genic regulation can be located through in vitro tranfections and in vivo transgenic mouse studies. Dr. Susan Henning's laboratory, whose primary focus is intestinal development, is an excellent environment in which to develop this proposal. Because BA absorption is immature in human infants as well as in suckling rats, this project may provide clinical application to managing neonates, especially those who are premature.