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。虽然移植是一小部分选定患者的替代选择，但显然仍然需要旨在增加残肠功能的策略。小肠表面积减少后，肠道会发生适应性反应，其特征是隐窝细胞增生、绒毛延长和吸收功能增强。该项目的最终目标是阐明适应性反应的机制，以促进合理的营养和药理学方案的设计，以最大限度地提高肠道适应性。在目前的资助期，我们已经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剂的重要性。最令人信服的支持性证据包括观察到缺乏维生素A会损害适应，而服用维生素A会增强适应。以下假设将在本提案中得到解决：1 .类维生素a通过影响细胞死亡、隐窝细胞增殖、上皮细胞粘附和迁移，直接调节肠道对功能肠面积丧失的适应性反应。2. 类视黄醇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/或其他核受体相互作用（异源二聚化）是类视黄醇调节适应的重要机制。3. 类维生素a通过影响凋亡调节因子Bcl2/Bax家族抑制适应性肠道细胞凋亡。具体目标是：1。通过研究维生素A在啮齿动物切除模型中的作用，确定维生素A调节肠道适应的机制。1一个。定义改变外源性类维生素a的时间和剂量对适应性反应的开始、维持和增强的影响。明确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异源二聚化与RARs、ppar和farnesoid X受体的作用，明确维生素A在适应中的作用机制。3. 通过研究类维生素A如何影响肠道细胞凋亡途径来确定维生素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.