Inflammation and Glucose Sensor Function

背景：为糖尿病患者开发植入式血糖传感器已经投入了大量的精力，但目前的传感器由于功能丧失，只能使用数小时至数天。这种传感器功能的丧失部分是由于葡萄糖传感器周围的炎症、纤维化和血管退化这三种组织反应的结果。由于肥大细胞在所有这些过程中起着关键作用，我们提出了以下假设：肥大细胞及其激活产物，通过释放直接生物污染葡萄糖传感器的药物，以及释放促进炎症和组织损伤的促炎剂（例如肥大细胞衍生的血管活性因子和趋化因子），直接或间接地导致体内葡萄糖传感器功能的丧失，从而导致体内传感器功能的短期和长期丧失。研究设计：使用我们最近开发的植入式葡萄糖传感器小鼠模型，我们将确定肥大细胞的缺失和/或抑制及其产生对体内传感器功能的影响。特异性目标：特异性目标1：确定肥大细胞和肥大细胞活化在体内葡萄糖传感器功能丧失和寿命中的作用特异性目标2：确定肥大细胞（MCs）及其产物对体外葡萄糖传感器功能的直接影响特异性目标3：确定肥大细胞衍生因子在体内和体外导致葡萄糖传感器功能丧失。

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.