NUTRIENT MODULATION OF GENE EXPRESSION IN GUT ADAPTATION

肠道吸收功能受损是发病的主要原因 以及生活质量受损，从而导致医疗保健成本增加。 这一问题通常是由功能丧失的肠道引起的 表面积，发生在临床情况下，如肠炎 血管疾病、创伤或继发于肠道切除的疾病 先天性和新生儿疾病，以及艾滋病等慢性疾病 肠病。目前，对于许多这样的患者来说，唯一的选择是 终身依赖肠外营养。虽然是小肠 移植可能很快就会成为选定患者的一种选择， 旨在增加肠道吸收功能的策略 需要嫁接。在小肠表面积丧失后， 肠道经历了以隐窝细胞为特征的适应性反应 增生，绒毛延长，吸收功能增强。 尽管腔内营养是发生适应所必需的，但几乎不需要。 了解潜在的分子和细胞机制。几个 实验观察表明，类维甲酸可能是重要的 肠道细胞增殖和分化的营养调节 在正常的和适应的肠道中。 该项目的最终目标是设计合理的营养和 在减少的情况下最大限度地适应的药物治疗方案 功能性肠道表面积。 这项提议的假设是：1.类维甲酸和其他营养物质可以 直接调节肠道对功能丧失的适应性反应 肠道表面积。2.这些营养物质通过局部和全身 机制，通过改变细胞的遗传程序发挥这些作用 肠上皮细胞位于隐窝和绒毛上。3. 营养物质对适应的基因组效应鉴定 肠道将促进临床方案的优化设计 以最大限度地提高肠道对疾病和切除的适应性反应。 为了检验这些假设，这一提议的具体目标是：L。 评价维甲酸增强肠道适应性的能力 回应。这将通过检查形态测量响应来评估 (绒毛高度、隐窝深度、隐窝细胞产生和肠腺细胞 迁移率)和一组大鼠基因的表达模式 在适应回肠残端诱导的基础上进行克隆 在70%的肠切除后。2.鉴定肠道基因 维甲酸在正常和适应残留物中的特异性调节 70%切除后的肠道--以及在人肠道Caco-2细胞中 排队。

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.