Interstitial Cells of Cajal in Diabetic Gastropathy

描述（由申请方提供）：在胰岛素依赖型和非胰岛素依赖型糖尿病约10年后，30-60%的患者报告了由糖尿病胃病和胃轻瘫（胃病的不可逆终末期形式）引起的上消化道症状。这些胃运动异常可能严重影响患者的生活质量，可能影响血糖控制，偶尔可能导致失能症状，如营养不良，水和电解质失衡，甚至误吸。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仍不清楚。在本提案中，我们提供了一个新的假设。最近，Cajal间质细胞（ICC），一种存在于胃的肌间区域（ICC-MY）和平滑肌层（ICC-IM）内的间充质细胞类型，已被确定分别为神经传递的起搏器和介质。由于这两种功能在糖尿病胃病中受到严重影响，因此ICC网络的破坏可能是这种疾病的某些病理变化特征的基础。我们发表的工作和使用非肥胖的自发性糖尿病（NOD）小鼠的额外的初步研究，以及最近关于糖尿病的人胃肠道并发症的报告（He等人，Gastroenterology 121：427-434，2001）支持该假设的有效性。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。本课题拟利用该模型研究：（1）糖尿病胃轻瘫患者胃内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障碍;（二）研究糖尿病NOD小鼠胃中ICC耗竭是否是由于高血糖或低胰岛素血症，并研究这些因素影响的机制。ICC表型和功能;和（3）检查导致远端胃中ICC减少的细胞机制（例如凋亡、坏死或转分化）。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.