NUTRIENT MODULATION OF GENE EXPRESSION IN GUT ADAPTATION

肠吸收功能受损是发病的主要原因 生活质量受损，导致医疗保健费用增加。 这个问题，这往往是由于失去功能的肠道 表面积，发生在这样的临床情况下，炎症肠 疾病、继发于血管疾病、创伤或 先天性和新生儿疾病以及艾滋病等慢性疾病 肠病目前，许多患者的唯一选择是 终生依赖肠外营养。 虽然小肠 移植可能很快成为选定患者的替代方案， 旨在增加肠道吸收功能的策略 需要移植。小肠表面积减少后， 肠经历以隐窝细胞为特征的适应性反应 增生、绒毛延长和吸收功能增加。 虽然发生适应需要内腔营养， 了解潜在的分子和细胞机制。几 实验观察表明类维生素A可能是重要的 肠细胞增殖和分化的营养调节剂 在正常和适应性肠道中。 该项目的最终目标是设计合理的营养和 药理学方案，以最大限度地适应在减少 功能性肠表面积。 本研究假设：1.类维生素A和其他营养素可以 直接调节肠道对功能丧失的适应性反应 肠表面积2.这些营养物质，通过局部和全身 机制，发挥这些影响，通过改变遗传程序的 肠上皮细胞位于隐窝和绒毛上。3. 确定营养物质对适应性的基因组效应 肠道将有助于优化临床方案设计 以最大化肠道对疾病和切除的适应性反应。 为了验证这些假设，本提案的具体目标是：到 评估类维生素A增强肠道适应性的能力 反应这将通过检查形态学反应进行评估 （绒毛高度、隐窝深度、隐窝细胞产生和肠上皮细胞 迁移率）和大鼠基因组的表达模式 克隆的基础上，他们的诱导，在适应回肠残余 切除了70%的肠 2.来鉴定肠道基因 在正常和适应性残体中由视黄酸特异性调节 在70%切除后的小肠中，以及在人小肠Caco-2细胞中， 线

Impairment of intestinal absorptive function is a major cause of morbidity and impaired quality of life, which lead to increased health care costs. This problem, which often results from loss of functional intestinal surface area, occurs in such clinical situations as inflammatory bowel disease, intestinal resection secondary to vascular disease, trauma or congenital and neonatal disorders, and chronic disorders such as AIDS enteropathy. Currently the only option for many of these patients is lifelong dependence on parenteral nutrition. Although small intestinal transplantation may soon become an alternative for selected patients, strategies designed to increase the absorptive function of intestinal grafts are needed. Following loss of small bowel surface area, the intestine undergoes an adaptive response characterized by crypt cell hyperplasia, villus lengthening, and increased absorptive function. Although lumenal nutrients are required for adaptation to occur, little is known about the underlying molecular and cellular mechanisms. Several experimental observations indicate that retinoids may be important nutrient regulators of intestinal cell proliferation and differentiation in the normal and adapting gut. The ultimate goal of this project is to design rational nutritional and pharmacological regimens to maximize adaptation in the setting of reduced functional intestinal surface area. The hypotheses of this proposal are: 1. Retinoids and other nutrients can directly modulate the intestinal adaptive response to loss of functional bowel surface area. 2. These nutrients, through both local and systemic mechanisms, exert these effects by altering the genetic program of the intestinal epithelial cells located in the crypt and on the villus. 3. Identification of the genomic effects of nutrients on the adapting intestine will facilitate the optimization of clinical regimens designed to maximize the intestinal adaptive response to disease and resection. To test these hypotheses, the specific aims of this proposal are: l. To evaluate the ability of retinoids to augment the intestinal adaptive response. This will be assessed by examining the morphometric response (villus height, crypt depth, and crypt cell production and enterocyte migration rates) and the pattern of expression of a cohort of rat genes cloned on the basis of their induction in the adapting ileal remnant following 70% intestinal resection. 2. To identify intestinal genes specifically regulated by retinoic acid in the normal and adapting remnant intestine following 70% resection-and in the human intestinal Caco-2 cell line.