Nutrient Modulation of Gene Expression In Gut Adaptation

描述(由申请人提供)：由肠道吸收功能减弱引起的短肠综合征是发病率和生活质量受损的主要原因。尽管移植是选定的一小部分患者的替代方案，但显然仍需要设计出增加残肠功能的策略。随着小肠表面积的丧失，肠道经历了以隐窝细胞增生、绒毛延长和吸收功能增强为特征的适应性反应。该项目的最终目标是阐明适应性反应的潜在机制，以促进合理的营养和药物方案的设计，以最大化肠道适应。在当前的赠款期间，我们使用啮齿动物切除模型来确认维生素A作为适应性反应的假定调节器的重要性。最令人信服的支持性证据包括观察到维生素A缺乏会损害适应，而维生素A的使用会增强适应。目前的方案将涉及以下假设：1.维甲酸通过影响细胞死亡以及隐窝细胞的增殖、上皮细胞的黏附和迁移，直接调节肠道对功能性肠区丧失的适应性反应。2.视黄酸X受体(RXR)与视黄酸受体(RAR)、过氧化物酶体增殖物激活受体(PPAR)和/或其他核受体的相互作用(异源二聚化)是维甲酸调节适应的重要机制。3.维甲酸通过作用于Bcl2/Bax家族的凋亡调节因子，抑制适应性肠道中的细胞凋亡。研究的具体目的是：1.通过观察维生素A对啮齿动物切除模型的影响，明确维生素A调节肠道适应的机制。1.确定不同的外源性维甲酸的时间和剂量对启动、维持和增强适应性反应的影响。IB定义了CRBP II和维生素A代谢在肠道适应中的作用。2.通过研究RARs和RXR与RARs、PPAR和法尼醇X受体的异构化作用，明确维生素A在适应中的作用机制。3.通过研究维甲酸如何影响肠道中的细胞凋亡途径，确定维生素A在适应中的作用机制。

DESCRIPTION (provided by applicant): Short bowel syndrome resulting from diminished intestinal absorptive function is a major cause of morbidity and impaired quality of life. Although transplantation is an alternative for a small subset of selected patients, strategies designed to increase the function of the remnant intestine are clearly still needed. Following loss of small bowel surface area, the gut undergoes an adaptive response characterized by crypt cell hyperplasia, villus lengthening, and increased absorptive function. The ultimate goal of this project is to elucidate the mechanisms underlying the adaptive response to facilitate the design of rational nutritional and pharmacological regimens to maximize gut adaptation, hi the current grant period, we have used rodent resection models to confirm the importance of vitamin A as a putative regulator of the adaptive response. The most compelling supportive evidence includes observations that vitamin A deficiency impaired adaptation and vitamin A administration augmented adaptation. The following hypotheses will be addressed in the current proposal: l.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. 2. Retinoid X Receptor (RXR) interactions (heterodimerization) with retinoic acid receptors (RAR), peroxisome proliferator activated receptors (PPAR), and/or other nuclear receptors are an important mechanism for retinoid modulation of adaptation. 3. Retinoids inhibit apoptosis in the adapting gut via effects on the Bcl2/Bax family of apoptotic regulators. The specific aims are: 1. Define the mechanisms by which vitamin A modulates intestinal adaptation by investigating the effects of vitamin A administration in rodent resection models. 1 A. Define the effects of varying the timing and dosing of exogenous retinoids on the initiation, maintenance and enhancement of the adaptive response. IB Define the role of CRBP II and vitamin A metabolism in intestinal adaptation. 2. Define the mechanisms of vitamin A actions in adaptation by studying the role of RARs and RXR heterodimerization with RARs, PPARs and farnesoid X receptors. 3. Define the mechanisms of vitamin A actions in adaptation by studying how retinoids affect apoptotic pathways in the gut.