Mast cell effects on islet cell destruction in NOD mice

描述(申请人提供)：肥大细胞是一种有效的炎性细胞，在过敏研究领域得到了最好的研究。最近的证据表明，肥大细胞在多发性硬化症和关节炎等自身免疫性疾病的小鼠模型中发挥了作用。肥大细胞通常存在于胰腺中，在胰腺炎等炎症性疾病中肥大细胞数量增加。此外，它们也是调节T细胞反应的重要介质的重要生产者，T细胞反应启动了导致糖尿病的炎症。据推测，肥大细胞影响导致胰岛β细胞破坏的炎症事件。为了测试这一点，我们将利用肥大细胞缺陷的小鼠模型。导致肥大细胞缺陷表型(两个不同的cKit突变)的基因将被培育到NOD/LT小鼠背景上，并将评估其对糖尿病前期和糖尿病指数的影响。其具体目的是：1.建立和鉴定肥大细胞缺陷NOD小鼠品系；2.研究肥大细胞缺陷在自发性胰腺炎和糖尿病发病中的作用。3.明确肥大细胞在糖尿病发病中的作用部位。

DESCRIPTION (provided by applicant): Mast cells are potent inflammatory cells that have been best studied in the realm of allergy research. Recent evidence has established a role for mast cells in murine models of autoimmune diseases such as multiple sclerosis and arthritis. Mast cells are normally present in the pancreas and increase in numbers in inflammatory conditions of the pancreas such as pancreatitis. In addition, they are important producers of mediators that are known to regulate T cell responses that initiate the inflammation that contributes to diabetes. It is hypothesized that mast cells influence inflammatory events that lead to pancreatic islet beta cell destruction. To test this, we will utilize a mast cell-deficient mouse model. Genes that give rise to a mast cell-deficient phenotype (two distinct ckit mutations) will be bred onto the NOD/Lt mouse background and the effects on indices of pre-diabetes and diabetes will be evaluated. The specific aims are: 1. To develop and characterize a line of mast cell-deficient NOD mice 2. To examine the consequencess of mast cell-deficiency on the development of spontaneous insulitis and diabetes. 3. To determine the sites of mast cell influence on diabetes development.