Inflammation and Glucose Sensor Function

描述(申请人提供)：背景：为糖尿病患者开发植入式葡萄糖传感器已经投入了大量的努力，但由于功能丧失，目前的传感器只能使用几小时到几天。传感器功能的丧失在一定程度上是葡萄糖传感器周围的炎症、纤维化和血管退化三种组织反应的结果。由于肥大细胞在所有这些过程中发挥了关键作用，我们提出了如下假说Grant假说：肥大细胞及其激活产物直接和间接地导致体内葡萄糖传感器功能的丧失，通过释放直接影响葡萄糖传感器的物质，以及通过释放促炎因子(例如肥大细胞衍生的血管活性和趋化因子)来促进炎症和组织损伤，从而导致体内短期和长期传感器功能的丧失。研究设计：利用我们最近开发的植入式葡萄糖传感器的小鼠模型，我们将在体内确定肥大细胞的缺失和/或抑制及其产生对传感器功能的影响。特异性目的：特异性目的1：确定肥大细胞和肥大细胞激活在体内葡萄糖传感器功能丧失和寿命中的作用。目的2：确定肥大细胞(MC)及其产物在体外对葡萄糖传感器功能的直接影响。

DESCRIPTION (provided by applicant): Background: Significant effort has been invested in developing implantable glucose sensors for diabetics, but current sensors last only hrs to days due to loss of function. This loss of sensor function is in part the result of the tissue response triad of inflammation, fibrosis and vessel regression surrounding the glucose sensor. Since mast cells play a key role in all these processes we have developed the following hypothesis Grant Hypothesis: Mast cells, and their activation products, directly and indirectly contribute to the lose of glucose sensor function in vivo, by releasing agents that directly biofoul glucose sensors, as well as by releasing pro-inflammatory agents (e.g. mast cell derived vasoactive and chemotactic factors) that promote inflammation and tissue injury, and thereby are responsible for loss of sensor function both short term and long term in vivo. Study Design: Using our recently developed mouse model of implantable glucose sensors we will determine the impact of deletion and or inhibition of mast cells and the production on sensor function in vivo. Specific Aims: SPECIFIC AIM 1: To Determine the Role of Mast Cells and Mast Cell Activation, in the Loss of Glucose Sensor Function and Lifespan in Vivo SPECIFIC AIM 2: To Determine the Direct Impact of Mast Cells (MCs), and MCs Products, on Glucose Sensor Function in Vitro SPECIFIC AIM 3: To Identify Mast Cell Derived Factors that Contribute to the Loss of Glucose Sensor Function in Vivo and in Vitro.