Interstitial Cells of Cajal in Diabetic Gastropathy

糖尿病胃病中的卡哈尔间质细胞

• 批准号: 6791263
• 负责人: Tamas Ordog
• 金额: $ 21.75万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6791263
• 关键词: NOD mouse; apoptosis; cell differentiation; diabetes mellitus; disease /disorder etiology; enteric nervous system; medical complication; necrosis; neural information processing; neuroregulation; paralysis; pathologic process; stomach; stomach disorder; stomach emptying; stomach motility /pressure

DESCRIPTION (provided by applicant): Upper gastrointestinal symptoms arising from diabetic gastropathy, and gastroparesis, the irreversible, end-stage form of gastropathy, have been reported in 30-60% of patients after approximately 10 years of both insulin-dependent and non-insulin-dependent diabetes mellitus. These gastric motor abnormalities can seriously affect the patients' quality of life, may affect glycemic control and can occasionally result in incapacitating symptoms like malnutrition, water and electrolyte imbalance or even aspiration. Most basic and clinical scientists view these complications of diabetes as a manifestation of autonomic neuropathy but their exact pathomechanism remains unclear. In the present proposal we offer a novel hypothesis. Recently, interstitial cells of Cajal (ICC), a mesenchymal cell type residing in the myenteric region (ICC-MY) and within smooth muscle layers (ICC-IM) of the stomach, have been identified as pacemakers and mediators of neurotransmission, respectively. Because both functions are seriously affected in diabetic gastropathy, it is possible that disruption of ICC networks could underlie some of the pathological changes characteristic of this disease. Our published work and additional preliminary studies using non-obese, spontaneously diabetic (NOD) mice, as well as a recent report about the human gastrointestinal complications of diabetes (He et al., Gastroenterology 121: 427-434, 2001) support the validity of this hypothesis. Thus, NOD mice offer an exciting new animal model for studies of diabetic gastropathy. In this project we plan to characterize and use this model to: (1) study how networks of gastric ICC are altered in diabetic gastroparesis and how alterations in ICC-MY number and distribution could lead to gastric arrhythmias and impaired gastric emptying; (2) to investigate whether ICC depletion in the stomach of diabetic NOD mice is due to hyperglycemia or hypoinsulinemia and to study the mechanisms by which these factors influence ICC phenotype and function; and (3) to examine what cellular mechanisms (e.g. apoptosis, necrosis or transdifferentiation) lead to the reduction of ICC in the distal stomach. The proposed experiments could provide the basic concepts needed for the development of novel, more effective treatment options for patients with diabetic gastropathy.

描述（由申请人提供）：据报道，在胰岛素依赖型和非胰岛素依赖型和非胰岛素依赖型胃病大约 10 年后，30-60% 的患者会出现由糖尿病性胃病和胃轻瘫（胃病的不可逆转的终末期形式）引起的上消化道症状。胰岛素依赖型糖尿病。这些胃运动异常会严重影响患者的生活质量，可能影响血糖控制，有时会导致营养不良、水和电解质失衡甚至误吸等失能症状。大多数基础科学家和临床科学家将糖尿病的这些并发症视为自主神经病变的表现，但其确切的病理机制仍不清楚。在本提案中，我们提出了一个新颖的假设。最近，Cajal 间质细胞 (ICC) 是一种存在于肌间区 (ICC-MY) 和胃平滑肌层 (ICC-IM) 内的间质细胞类型，已被确定分别为神经传递的起搏器和介质。由于糖尿病性胃病的两种功能均受到严重影响，因此 ICC 网络的破坏可能是该疾病特征性病理变化的基础。我们发表的工作和使用非肥胖自发性糖尿病 (NOD) 小鼠的其他初步研究，以及最近关于糖尿病人类胃肠道并发症的报告（He 等人，Gastroenterology 121: 427-434, 2001）支持了有效性这个假设。因此，NOD 小鼠为糖尿病胃病的研究提供了一种令人兴奋的新动物模型。在本项目中，我们计划表征并使用该模型来：（1）研究胃 ICC 网络在糖尿病性胃轻瘫中如何改变，以及 ICC-MY 数量和分布的改变如何导致胃心律失常和胃排空受损； (2) 探讨糖尿病NOD小鼠胃内ICC耗竭是否是由高血糖或低胰岛素血症所致，并研究这些因素影响ICC表型和功能的机制； (3) 检查哪些细胞机制（例如细胞凋亡、坏死或转分化）导致远端胃 ICC 减少。拟议的实验可以为糖尿病胃病患者开发新颖、更有效的治疗方案提供所需的基本概念。