AMINO ACID TRANSPORT AFTER SMALL BOWEL RESECTION

小肠切除术后的氨基酸转运

• 批准号: 6380874
• 负责人: HARRY CHARLES SAX
• 金额: $ 48.56万
• 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/6380874
• 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.

短肠综合症是一种破坏性的临床疾病， 导致脱水、肌肉萎缩、衰弱和死亡。虽然 残余肠有能力适应其减少的表面积，这 该过程通常是不充分的，可能需要终生完全注射 营养，一种具有严重代谢和经济后果的方式。生长 因素可以部分通过增加肠上皮细胞的能力来改善适应 运输管腔营养物质。主要营养素谷氨酰胺（GLN）是主要营养物质 肠上皮细胞的氧化燃料。表皮注射给药 生长因子 (EGF) 和/或人类生长激素 (GH) 增加钠依赖性 兔 70% 肠切除术后谷氨酰胺转运。具体时间安排， 给药途径、作用机制和潜在的协同作用 这两种化合物的作用仍有待阐明。 EGF结合激活 EGF受体（EGFR）。在来自人类空肠的细胞悬液中 和C2BBE1细胞系，EGF增加谷氨酰胺转运，上调被阻断 通过酪氨酸激酶抑制剂，暗示 EGFR 信号传导的作用 转导途径。 GH 也可能独立地通过 EGFR 发挥作用。这是 假设 EGF 和 GH 的组合上调钠依赖性 谷氨酰胺通过 EGFR 信号转导途径转运。具体的 该提案的目的是 1) 优化 EGF/GH 介导的谷氨酰胺转运 在大肠切除术后通过 EGFR 检测兔子； 2）确定参与程度 EGFR 信号转导途径通过 EGF/GH 改变谷氨酰胺转运的研究 C2BBE1细胞系中的暴露； 3) 通过EGFR研究EGF/GH的作用 上调人类小肠中谷氨酰胺的转运。调查人员 计划使用三种小肠功能模型：70%肠切除术 兔、Transwell 中的人细胞系 C2BBE1 和人小肠作为 肠细胞悬浮液或作为神经血管完整的环。据推测 更好地理解生长因子诱导的机制 营养物质运输的上调将具有重大的临床意义 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。