NUTRIENT MODULATION OF GENE EXPRESSION IN GUT ADAPTATION

这是竞争性续订R 01的第一个版本 应用程序.随着小肠表面积的减少， 经历适应性反应，其特征在于隐窝细胞增生、绒毛 延长和增加吸收功能。关于这一点，我们知之甚少。 这种适应的潜在分子和细胞机制。最终 本项目的目标是阐明这些机制，以促进设计 营养和药物方案，以最大限度地提高肠道适应性。 研究者此前曾使用大鼠肠道切除模型克隆 一组在适应性残留肠道中受到调节的基因。这些 研究表明，维生素A是适应性免疫系统的潜在调节剂。 反应其他证据支持维生素A在适应中的作用， 来自目前的支持期，证明：（1）维甲酸 在术后早期刺激隐窝细胞增殖， 适应;（2）维生素A缺乏症的诱导完全阻断了 适应性反应;（3）维生素A缺乏可能会损害适应性， 刺激细胞凋亡。初步研究表明， 程序性细胞死亡是适应性反应的重要贡献者。的 本订正提案将处理以下假设：（1） 程序性细胞死亡率的改变有助于肠道 适应性反应这些改变是由BcL 2/Bax家族介导的， 凋亡调节因子;（2）维甲酸直接调节肠道适应性 通过对细胞死亡的影响对功能性肠区丧失的反应，以及 隐窝细胞增殖、上皮细胞粘附和迁移。具体 本研究的目的是：（1）明确细胞凋亡的作用， 利用Bcl-2和Bax研究肠适应中细胞凋亡的近端调节因子 敲除小鼠和转基因小鼠，在小细胞中过表达Bcl-2， 肠。(2a)定义类维生素A在启动和维持 通过研究维生素A给药对 细胞增殖和凋亡。(2b)定义维生素A 通过分析小肠切除术后缺乏损害适应 细胞凋亡、细胞粘附和细胞外基质的改变。的 研究者还将确定CRBP II表达早期变化是否 通过检查适应性反应，反映适应中的调节作用， CRBP II敲除小鼠。

This is the first revision of a competitive renewal R01 application. Following the loss of small bowel surface area, the intestine undergoes an adaptive response characterized by crypt cell hyperplasia, villus lengthening and increased absorptive function. Little is known of the underlying molecular and cellular mechanisms of this adaptation. The ultimate goal of this project is to elucidate these mechanisms to facilitate the design of nutritional and pharmacological regimens to maximize intestinal adaptation. The investigator has previously used a rat intestinal resection model to clone a group of genes that are regulated in the adapting remnant intestine. These studies have implicated vitamin A as a potential regulator of the adaptive response. Additional evidence supporting a role for vitamin A in adaptation has come from the current support period demonstrating that: (1) retinoic acid stimulates crypt cell proliferation in the early postoperative phase of adaptation; (2) the induction of vitamin A deficiency completely blocks the adaptive response; and (3) vitamin A deficiency may impair adaptation by stimulating apoptosis. Preliminary studies have implicated modulation of programmed cell death as an important contributor to the adaptive response. The following hypotheses will be addressed in this revised proposal: (1) alterations in the rate of programmed cell death contribute to the intestinal adaptive response. These alterations are mediated by the BcL2/Bax family of apoptosis regulators; (2) retinoids directly modulate the intestinal adaptive response to loss of functional bowel area via effects on cell death, as well as crypt cell proliferation, epithelial cell adhesion and migration. The specific aims of this proposal are: (1) To define the role of apoptosis and identify proximal regulators of apoptosis in gut adaptation, using Bcl-2 and Bax knockout mice and transgenic mice that overexpress Bcl-2 in the small intestine. (2a) Define the role of retinoids in initiating and maintaining the adaptive response by investigating the effects of vitamin A administration on cell proliferation and apoptosis. (2b) Define the mechanisms by which vitamin A deficiency impairs adaptation following small bowel resection by analyzing alterations in apoptosis, cell adhesion and the extracellular matrix. The investigator will also determine whether early changes in CRBP II expression reflect a regulatory role in adaptation by examining the adaptive response in CRBP II knockout mice.