AMINO ACID TRANSPORT AFTER SMALL BOWEL RESECTION

小肠切除术后的氨基酸转运

• 批准号: 6044866
• 负责人: HARRY CHARLES SAX
• 金额: $ 45.08万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6044866
• 关键词: aminoacid transport; biological signal transduction; dietary aminoacid; epidermal growth factor; gastrointestinal absorption /transport; gastrointestinal function; gastrointestinal nutrient absorption; glutamine; growth factor receptors; hormone regulation /control mechanism; human tissue; immunoprecipitation; in situ hybridization; intestinal villi; intestine surgery; jejunectomy /duodenectomy /ileectomy; laboratory rabbit; membrane transport proteins; nutrition related tag; postoperative state; receptor binding; small intestines; somatotropin; tissue /cell culture; western blottings

Short bowel syndrome is a devastating clinical condition which leads to dehydration, muscle wasting, debilitation and death. Although the residual bowel has the capacity to adapt to its reduced surface area, this process is often inadequate and may require lifetime total parenteral nutrition, a modality with serious metabolic and economic consequences. Growth factors can improve adaptation in part by increasing the enterocyte's ability to transport luminal nutrients. A major nutrient glutamine (GLN) is the primary oxidative fuel for the enterocyte. The parenteral administration of epidermal growth factor (EGF) and/or human growth hormone (GH) increases sodium-dependent glutamine transport after 70% enterectomy in rabbits. The specific timing, route of administration, mechanisms of action, and potential synergistic effects of these two compounds remain to be elucidated. EGF binding activates the EGF receptor (EGFR). In cell suspensions derived from both human jejunum and C2BBE1cell line, EGF increases glutamine transport, upregulation is blocked by tyrosine kinase inhibitors which implicates a role for EGFR signaling transduction pathways. GH independently may also act through EGFR. It is hypothesized that the combination of EGF and GH upregulate sodium-dependent glutamine transport through EGFR signal transduction pathways. The specific aims of the proposal are to 1) optimize glutamine transport mediated by EGF/GH through EGFR in rabbits after massive enterectomy; 2) determine the involvement of EGFR signal transduction pathways in altering glutamine transport by EGF/GH exposure in C2BBE1cell line; 3) to investigate the effects of EGF/GH via EGFR in upregulating glutamine transport in human small bowel. The investigators plan to use three models of small bowel function: 70% enterectomy in the rabbit, the human cell line C2BBE1 in Transwells and human small bowel as an enterocyte suspension or as a neurovascularly intact loop. It is hypothesized that a better understanding of mechanisms involved in growth factor induced upregulation of nutrient transport will have significant clinical implications in developing safe and innovative strategies to treat patients with short bowel syndrome and other malabsorptive states.

短肠综合征是一种毁灭性的临床症状， 会导致脱水、肌肉萎缩、虚弱和死亡。尽管 残留肠有能力适应其减少的表面积，这 这个过程往往不充分，可能需要终生完全的肠外支持 营养，一种具有严重新陈代谢和经济后果的方式。生长 因子可以部分地通过增加肠道细胞的能力来改善适应 来运输管腔营养物质。谷氨酰胺(Gln)是一种主要的营养物质 肠道细胞的氧化燃料。表皮的非肠道给药 生长因子和/或人生长激素增加钠依赖 兔70%肠切除后谷氨酰胺转运。具体的时间， 管理途径、作用机制和潜在的协同效应 这两个化合物的作用还有待阐明。EGF结合被激活 表皮生长因子受体(EGFR)。取自人空肠和空肠的细胞悬液 和C2BBE1细胞株，EGF促进谷氨酰胺转运，上调被阻断 通过酪氨酸激酶抑制剂，这暗示了EGFR信号转导的作用 转导通路。GH独立也可能通过EGFR发挥作用。它是 假设EGF和GH联合作用可上调钠依赖 谷氨酰胺通过EGFR信号转导途径转运。具体的 该方案的目的是：1)优化EGF/GH介导的谷氨酰胺转运 通过大肠切除后兔的EGFR；2)确定受累程度 表皮生长因子/生长激素影响谷氨酰胺转运的EGFR信号转导通路研究 在C2BBE1细胞中暴露；3)通过EGFR研究EGF/GH的作用 在上调人体小肠谷氨酰胺转运方面。调查人员 计划使用三种模式的小肠功能：美国70%的肠切除 兔、人T细胞系C_2BBE_1和人小肠 肠细胞悬浮液或作为神经血管完整的环。这是假设的 更好地理解生长因子诱导 营养物质转运的上调将具有重要的临床意义 开发安全和创新的策略来治疗短肠患者 综合征和其他吸收不良状态。