SURGICAL STUDIES ON METABOLISM OF GI HORMONES

当今胃肠研究的一个主要挑战是更好地了解维持外分泌胰腺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。人类严重的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，黏膜疾病或损伤后缺乏适当的肠道再生或适应可能与临床相关。小肠粘膜的特化上皮细胞是营养吸收、免疫功能和调节体液和电解质平衡的重要器官。通过炎症、浸润、手术切除或缺血破坏肠黏膜的完整性会导致严重的吸收不良，最终导致临床营养不良，需要全肠外营养支持。这项工作的长期目标是了解胃肠道激素在胰腺稳态中所起的作用，以及在控制胃肠道上皮恢复和再生中的作用。本课题的具体目的是：1)研究胃肠激素在急性胰腺炎实验模型胰腺细胞凋亡和再生调控中的作用；2)确定胃肠激素在调节肠道适应性增生中的作用。提出的研究旨在以系统的方式精确定义GI激素相关的细胞内转导途径的组成部分，这些转导途径参与AP实验模型中胰腺凋亡和再生的调节；以及与肠道适应性增生相关的胃肠道黏膜增生。为了达到这些目的，我们将在三种不同的实验性AP模型中研究腺泡细胞增殖和凋亡的分子途径，以及神经紧张素介导的胰岛素样生长因子- i （IGF-I）调节神经紧张素基因表达和胰高血糖素样肽-2 (GLP-2)-刺激粘膜增殖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，旨在利用胃肠道激素在外分泌胰腺和肠粘膜上的独特生物活性。

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.