Islet Biology in Cystic Fibrosis Related Diabetes

描述（由申请人提供）：囊性纤维化相关糖尿病（CFRD）通常被认为是胰岛素缺乏和胰岛素抵抗的结果。然而，这种解释是不令人满意的，因为在CFRD的临床研究表明，胰岛素分泌不足，但很少有证据表明胰岛素抵抗。此外，普遍接受的胰岛素缺乏症的发病机制，即囊性纤维化（CF）胰腺炎和随后的胰腺萎缩和纤维化导致胰岛破坏，不太可能是一个充分的解释。由于囊性纤维化跨膜传导调节因子（CFTR）在小鼠和人胰岛细胞中表达和发挥功能，我们提出CFTR突变直接损害胰岛细胞功能和健康。在这项提案中，我们将测试CFTR在胰岛素和胰高血糖素分泌中起重要调节作用的假设，以及CFTR突变导致细胞功能障碍，细胞对胰岛“应激源”（胰腺炎，炎症，高血糖症）的适应不足，以及细胞质量减少，从而大大增加糖尿病的风险。我们提出了一个综合的，多组分的发病机制，涉及异常CFTR离子通道活性和异常CFTR蛋白运输和细胞生物学，导致分泌功能障碍，细胞内质网应激和细胞死亡。 我们的多学科团队具有电生理学，人类胰岛生物学和CF的专业知识，将使用独特的小鼠模型和人类胰岛进行体外和体内研究，以测试这些假设，并发现对理解人类CFRD发病机制重要的信息。我们将追求三个目标：1）通过研究缺乏CFTR的胰岛来确定CFTR在调节胰岛素和胰高血糖素分泌以及细胞功能和健康中的作用; 2）确定选定的CF突变对胰岛素和胰高血糖素分泌以及细胞功能和健康的影响;和3）确定选定的CF突变对细胞功能，健康和适应“胰岛应激源”，如胰腺炎，高血糖症，和胰岛素抵抗。

DESCRIPTION (provided by applicant): Cystic fibrosis-related diabetes (CFRD) is commonly thought to be a consequence of insulin deficiency combined with insulin resistance. However, this explanation is not satisfactory because clinical studies in CFRD show inadequate insulin secretion but little evidence for insulin resistance. Furthermore, the commonly accepted pathogenesis for the insulin deficiency, namely that the pancreatitis of cystic fibrosis (CF) and subsequent pancreatic atrophy and fibrosis lead to islet destruction, is not likely a sufficient explanation. Since the cystic fibrosis transmembrane conductance regulator (CFTR) is expressed and functional in mouse and human pancreatic islet cells, we propose that CFTR mutations directly impair islet cell function and health. In this proposal, we will test the hypotheses that CFTR plays an important regulatory role in insulin and glucagon secretion and that mutations in CFTR lead to � cell dysfunction, inadequate � cell adaptation to islet "stressors" (pancreatitis, inflammation, hyperglycemia), and reduced � cell mass, thus greatly increasing the risk for diabetes mellitus. We propose an integrated, multiple component pathogenesis involving abnormal CFTR ion channel activity and abnormal CFTR protein trafficking and cell biology, leading to secretory dysfunction, � cell ER stress, and � cell death. Our multidisciplinary team with expertise in electrophysiology, human islet biology, and CF will conduct in vitro and in vivo studies using unique mouse models and human islets to test these hypotheses and to discover information important for understanding the pathogenesis of human CFRD. We will pursue three aims: 1) Define the role of CFTR in regulating insulin and glucagon secretion and � cell function and health by studying islets lacking CFTR; 2)Determine the impact of selected CF mutations on insulin and glucagon secretion and � cell function and health; and 3) Determine the impact of selected CF mutations on � cell function, health, and adaptation in response to "islet stressors" such as pancreatitis, hyperglycemia, and insulin resistance.