Interstitial cells of Cajal in diabetic gastropathy

描述(申请人提供)：30%至60%的糖尿病患者有胃病和胃瘫的症状，例如消化不良、疼痛、反复恶心和呕吐以及随之而来的营养不良、血糖控制受损和生活质量下降。致病因素包括全身性和肌肉性神经病，可能导致幽门痉挛和眼底接受性松弛降低；平滑肌病，降低收缩能力；卡哈尔间质细胞(ICC)枯竭，导致电性心律失常和相性收缩减少，并导致神经肌肉神经传递受损。特发性胃轻瘫患者的ICC也减少。目前的治疗方法通常是不充分的，包括饮食、空肠造口或肠外喂养、注意血糖控制、胃减压、降低幽门张力，以及使用胃动力药物或电起搏刺激残余胃运动功能。重要的是，最近的数据表明，ICC降低的患者往往对药物治疗无效，对电刺激的反应也很差。因此，胃瘫患者可能会从预防ICC耗尽或替换丢失的细胞中受益。在这个项目中，我们将在动物和体外模型中探索以下预防和恢复ICC的方法：我们计划检查胰岛素和其他生长因子的治疗是否可以防止或恢复非肥胖糖尿病小鼠的这些细胞的丢失。胰岛素和其他生长因子对糖尿病患者是减少或无效的，但如果ICC是长期维持所必需的。我们的第二个目标是发展条件永生化的ICC，并检查这些细胞是否能够在器官型培养中恢复节律、电和收缩活动。最后，我们计划分离和鉴定ICC(“成体”干细胞)的承诺或多能前体细胞，检测它们在体外和体内的发展潜力，并研究它们在糖尿病和非糖尿病胃轻瘫小鼠中的调节和命运。拟议的实验可能会导致新的治疗选择，以恢复糖尿病或非糖尿病胃轻瘫患者失去的功能。与公共健康相关：胃轻瘫导致相当大比例的糖尿病患者的生活质量下降。目前的治疗目的是刺激残余功能，但往往是不够的。该项目的目标是开发新的治疗方法，专注于恢复或防止在这种疾病中减少的细胞的丢失。

DESCRIPTION (provided by applicant): Thirty to 60% of patients with diabetes mellitus suffer from symptoms of gastropathy and gastroparesis, e.g. dyspepsia, pain, recurring nausea and vomiting and consequent malnutrition, impaired glycemic control, and diminished quality of life. Pathogenetic factors include systemic and myenteric neuropathy, which may lead to pylorospasm and reduced receptive relaxation of the fundus; smooth myopathy, which reduces contractility; and depletion of interstitial cells of Cajal (ICC), which leads to electrical dysrhythmias and reduced phasic contractions and contributes to impaired neuromuscular neurotransmission. ICC are also reduced in idiopathic gastroparesis. Current therapeutic approaches, which are frequently inadequate, include diet, jejunostomy or parenteral feeding, attention to blood glucose control, gastric decompression, reducing pyloric tone, and stimulation of residual gastric motor function with gastrokinetic drugs or electrical pacing. Importantly, recent data indicate that patients with reduced ICC tend to be refractory to medical therapy and respond poorly to electrical stimulation. Thus, patients suffering from gastroparesis would likely benefit from prevention of ICC depletion or replacement of the missing cells. In this project we will explore, in animal and in vitro models, the following approaches to prevent and restore ICC: We plan to examine whether treatments with insulin and other growth factors, which are reduced or ineffective in diabetes but are required for the long-term maintenance if ICC, could prevent or restore the loss of these cells in nonobese diabetic mice. Our second aim is to develop conditionally immortalized ICC and examine whether these cells can restore rhythmic electrical and contractile activity in organotypic cultures. Finally, we plan to isolate and characterize committed or multipotent precursors of ICC ("adult" stem cells), examine their developmental potential in vitro and in-vivo, and study their regulation and fate in mice with diabetic and nondiabetic gastroparesis. The proposed experiments could lead to novel treatment options to restore function that is lost in patients with diabetic or nondiabetic gastroparesis. Relevance to public health: Gastroparesis causes diminished quality of life in a significant proportion of patients with diabetes. Current therapy aims at stimulating residual function and is frequently inadequate. The goal of this project is to develop novel treatments that focus on restoring, or preventing the loss of, cells that are reduced in this disorder.