NUTRIENT MODULATION OF GENE EXPRESSION IN GUT ADAPTATION

这是竞争续订R01的第一次修订 申请。随着小肠表面积的丧失，肠道 经历以隐窝细胞增生、绒毛为特征的适应性反应 拉长，增强吸收功能。人们对此知之甚少 这种适应的潜在分子和细胞机制。终极的 本项目的目标是阐明这些机制，以便于设计 营养和药物疗法，以最大限度地提高肠道适应能力。 研究人员此前曾使用大鼠肠道切除模型进行克隆 在适应的残肠中被调节的一组基因。这些 研究表明维生素A是一种潜在的适应性调节因子 回应。更多的证据支持维生素A在适应中的作用 来自当前支持期的数据表明：(1)维甲酸 在术后早期刺激隐窝细胞的增殖 适应；(2)维生素A缺乏的诱导完全阻断了 适应性反应；以及(3)维生素A缺乏可能通过以下方式损害适应性 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一个重要因素。这个 这份修订后的提案将提出以下假设：(1) 程序性细胞死亡速度的改变有助于肠道 适应性反应。这些改变是由bcl2/bax家族介导的 细胞凋亡调节剂；(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肠区丧失的反应，以及 隐窝细胞增殖、上皮细胞黏附和迁移。具体的 这项提议的目的是：(1)定义细胞凋亡的作用并确定 利用Bcl2和Bax研究肠道适应性中细胞凋亡的近端调节 小鼠中过表达Bcl-2的基因敲除小鼠和转基因小鼠 肠子。(2a)确定维甲酸在启动和维持 服用维生素A对大鼠适应性反应的影响 细胞增殖和凋亡。(2B)确定维生素A的作用机制 缺陷对小肠切除术后适应性损害的分析 细胞凋亡、细胞黏附和细胞外基质的变化。这个 研究人员还将确定CRBP II表达的早期变化 通过检查适应反应来反映适应中的调节作用 CRBP II基因敲除小鼠。

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.