Interstitial Cells of Cajal in Diabetic Gastropathy

描述(由申请人提供)：糖尿病胃病引起的上消化道症状，以及胃病的不可逆转的终末期形式胃瘫，在大约10年的胰岛素依赖型和非胰岛素依赖型糖尿病患者中都有30%-60%的报告。这些胃运动异常会严重影响患者的生活质量，可能会影响血糖控制，有时还会导致营养不良、水和电解质失衡甚至吸入等丧失能力的症状。大多数基础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，但它们的确切病理机制仍不清楚。在本提案中，我们提出了一个新的假设。近年来，Cajal间质细胞(ICC)是一种存在于胃肌间质区(ICC-MY)和平滑肌层(ICC-IM)内的间充质细胞，分别被认为是神经传递的起搏器和介体。由于这两种功能在糖尿病胃病中都受到严重影响，ICC网络的破坏可能是这种疾病特有的一些病理变化的基础。我们发表的工作和其他使用非肥胖自发性糖尿病(NOD)小鼠的初步研究，以及最近一份关于糖尿病引起的人类胃肠道并发症的报告(他等人，胃肠病学121：427-434,2001)支持这一假设的有效性。因此，NOD小鼠为糖尿病胃病的研究提供了一个令人兴奋的新动物模型。在本项目中，我们计划描述并使用这一模型来：(1)研究糖尿病胃轻瘫时胃ICC的网络是如何改变的，以及ICC-My的数量和分布的改变如何导致胃心律失常和胃排空障碍；(2)研究糖尿病NOD小鼠胃中ICC的耗竭是由于高血糖还是低胰岛素血症，并研究这些因素对ICC表型和功能的影响机制；以及(3)研究是什么细胞机制(如细胞凋亡、坏死或转分化)导致远端胃ICC的减少。拟议的实验可以为糖尿病胃病患者开发新的、更有效的治疗方案提供所需的基本概念。

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.