NUTRIENT MODULATION OF GENE EXPRESSION IN GUT ADAPTATION

描述（由研究者提供）：肠吸收功能减弱导致的短肠综合征是发病和生活质量受损的主要原因。虽然移植是一个选择的患者的一小部分的替代方案，旨在增加残肠的功能的策略显然仍然需要。在小肠表面积丧失后，肠道经历适应性反应，其特征在于隐窝细胞增生、绒毛延长和吸收功能增加。本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。在目前的资助期间，我们使用啮齿动物切除模型来证实维生素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维生素A缺乏损害适应和维生素A管理增强适应的观察。在本提案中将解决以下假设：1.类维生素A通过对细胞死亡以及隐窝细胞增殖、上皮细胞粘附和迁移的影响，直接调节对功能性肠区域丧失的肠适应性反应。2.类维生素A 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）是类维生素A调节适应的重要机制。3.类维生素A通过对凋亡调节因子的Bcl 2/Bax家族的影响来抑制适应性肠道中的凋亡。具体目标是：1.通过研究啮齿动物切除模型中维生素A给药的影响，确定维生素A调节肠道适应的机制。凌晨1定义外源性类维生素A的不同给药时间和剂量对适应性反应的启动、维持和增强的影响。IB定义CRBP II和维生素A代谢在肠道适应中的作用。2.通过研究RAR和RXR与RAR、PPARs和法尼醇X受体异源二聚化的作用，确定维生素A在适应中的作用机制。3.通过研究类维生素A如何影响肠道中的细胞凋亡途径，定义维生素A在适应中的作用机制。

DESCRIPTION (provided by investigator): 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.