SURGICAL STUDIES ON METABOLISM OF GI HORMONES

胃肠激素代谢的外科研究

• 批准号: 6145102
• 负责人: GUILLERMO GOMEZ
• 金额: $ 4.41万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6145102
• 关键词: acinar cell; apoptosis; biological signal transduction; cell proliferation; disease /disorder model; gastrointestinal epithelium; gastrointestinal hormones; gene expression; gene targeting; genetically modified animals; homeostasis; hormone regulation /control mechanism; hyperplasia; insulinlike growth factor; intestinal mucosa; laboratory mouse; laboratory rat; neurotensin; pancreatitis

A major challenge in gastrointestinal research today is to gain a better understanding of the underlying molecular mechanisms for maintenance of the exocrine pancreas and small bowel mucosa. Acute pancreatitis (AP) is a complex and poorly understood disease. Severe acute hemorrhagic or necrotizing pancreatitis in humans results in an exceptionally high morbidity and mortality. Despite the abundance of pancreatitis patients, underlying molecular mechanisms that control the severity of an AP are not known. Likewise, a deficiency in appropriate intestinal regeneration or adaptation following mucosal disease or injury can be clinically relevant. The specialized epithelial cells of the small bowel mucosa constitute an essential organ for nutrient absorption, immune function and regulation of fluid and electrolyte balance. Disruption of the integrity of the intestinal mucosa either through inflammation, infiltration, surgical resection or ischemia results in severe malabsorption and ultimately in clinical malnutrition requiring total parenteral nutritional support. The long term objectives of the proposed work are to understand the roles gastrointestinal (GI) hormones play in the homeostasis of the pancreas, and in controlling GI epithelial restitution and regrowth. The Specific Aims of this research proposal are: 1) to determine the role of gastrointestinal hormones in the regulation of pancreatic apoptosis and regeneration in experimental models of acute pancreatitis; and, 2) to determine the role of gastrointestinal hormones in the regulation of adaptive hyperplasia of the gut. The proposed studies are designed to precisely define, in a systematic fashion, the components of GI hormone-linked intracellular transduction pathways involved in the regulation of pancreatic apoptosis and regeneration in experimental models of AP; and, the proliferation of GI mucosa associated with adaptive hyperplasia of the gut. In order to accomplish these aims, we will investigate molecular pathways of acinar cell proliferation and apoptosis in three different models of experimental AP, and the intracellular signal transduction pathways mediating the regulation of neurotensin gene expression by insulin-like growth factor-I (IGF-I) and the enhancement of glucagon-like peptide-2 (GLP-2)- stimulated mucosal proliferation by neurotensin. These studies will provide a foundation for the development of innovative therapeutic strategies designed to exploit the unique biological activities of GI hormones on the exocrine pancreas and intestinal mucosa.

当今胃肠道研究的一个主要挑战是更好地了解维持胰腺外分泌和小肠粘膜的潜在分子机制。急性胰腺炎（AP）是一种复杂且知之甚少的疾病。人的严重急性出血性或坏死性胰腺炎导致异常高的发病率和死亡率。尽管有大量的胰腺炎患者，但控制AP严重程度的潜在分子机制尚不清楚。同样，粘膜疾病或损伤后适当的肠再生或适应的缺陷可能与临床相关。小肠粘膜的特化上皮细胞构成营养吸收、免疫功能以及调节液体和电解质平衡的重要器官。通过炎症、浸润、手术切除或局部缺血破坏肠粘膜的完整性导致严重的吸收不良，并最终导致需要全胃肠外营养支持的临床营养不良。这项工作的长期目标是了解胃肠道（GI）激素在胰腺稳态中的作用，以及控制GI上皮恢复和再生。本研究计划的具体目的是：1）确定胃肠激素在急性胰腺炎实验模型中胰腺细胞凋亡和再生调节中的作用; 2）确定胃肠激素在肠道适应性增生调节中的作用。拟议的研究旨在以系统的方式精确定义AP实验模型中参与胰腺细胞凋亡和再生调节的GI糖链相关细胞内转导途径的组分;以及与肠道适应性增生相关的GI粘膜增殖。为了实现这些目标，我们将研究在三种不同的实验性AP模型中腺泡细胞增殖和凋亡的分子途径，以及介导胰岛素样生长因子-I（IGF-I）调节神经降压素基因表达和增强胰高血糖素样肽-2（GLP-2）刺激的粘膜增殖的神经降压素的细胞内信号转导途径。这些研究将为开发创新的治疗策略提供基础，这些策略旨在利用GI激素对胰腺外分泌和肠粘膜的独特生物活性。