Interstitial Cells of Cajal in Diabetic Gastropathy

描述（由申请人提供）：据报道，30-60%的胰岛素依赖型和非胰岛素依赖型糖尿病患者在大约10年后出现由糖尿病性胃病和胃轻瘫（不可逆的终末期胃病）引起的上胃肠道症状。这些胃运动异常可严重影响患者的生活质量，影响血糖控制，偶尔可导致营养不良、水电解质失衡甚至误吸等失能症状。大多数基础和临床科学家认为糖尿病的这些并发症是自主神经病变的表现，但其确切的病理机制尚不清楚。在目前的建议中，我们提出了一个新的假设。最近，Cajal间质细胞（ICC）是一种位于胃肌区（ICC- my）和平滑肌层（ICC- im）内的间质细胞类型，已被确定分别作为起搏器和神经传递介质。由于这两种功能在糖尿病胃病中都受到严重影响，因此ICC网络的破坏可能是这种疾病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，以及最近关于糖尿病的人类胃肠道并发症的报告（He et al., Gastroenterology 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该模型：(1)研究糖尿病胃轻瘫中胃ICC网络的改变，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耗竭是由高血糖还是低胰岛素血症引起的，并研究这些因素影响ICC表型和功能的机制；(3)研究导致胃远端ICC减少的细胞机制（如凋亡、坏死或转分化）。所提出的实验可以为开发新的、更有效的糖尿病胃病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.