Islet Biology in Cystic Fibrosis Related Diabetes

描述(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合并胰岛素抵抗的结果。然而，这一解释并不令人满意，因为CFRD的临床研究显示胰岛素分泌不足，但几乎没有证据表明存在胰岛素抵抗。此外，普遍接受的胰岛素缺乏的发病机制，即囊性纤维性胰腺炎(CF)和随后的胰腺萎缩和纤维化导致胰岛破坏，可能不是一个充分的解释。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并具有功能，我们认为CFTR突变直接损害胰岛细胞的功能和健康。在这项提案中，我们将检验以下假设：CFTR在胰岛素和胰升糖素的分泌中起着重要的调节作用，CFTR的突变会导致细胞功能障碍，细胞对胰岛“应激因素”(胰腺炎、炎症、高血糖)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。我们提出了一种综合的、多组分的发病机制，涉及CFTR离子通道活性异常、CFTR蛋白运输异常和细胞生物学，导致分泌功能障碍、细胞内质网应激和细胞死亡。 我们的多学科团队拥有电生理学、人类胰岛生物学和CF方面的专业知识，将使用独特的小鼠模型和人类胰岛进行体外和体内研究，以检验这些假设，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，确定CFTR在调节胰岛素和胰升糖素分泌以及细胞功能和健康方面的作用；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；以及3)确定选定的CF突变对细胞功能、健康和应对“胰岛应激”(如胰腺炎、高血糖和胰岛素抵抗)的影响。 公共卫生相关性：囊性纤维化是高加索人最常见的遗传性疾病。大多数患者在2-3岁时被确诊，治疗的重点是提高存活率和生活质量，建议在囊性纤维化诊所进行，那里的肺、肠道和营养问题可以得到适当的处理。在过去的30年里，治疗的进步使寿命增加到40-50岁，囊性纤维化相关糖尿病(CFRD)已成为最常见的并发症。更好地了解导致CFRD的细胞和分子机制将是改善这一严重CF并发症的诊断和治疗的基础。

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. PUBLIC HEALTH RELEVANCE: Cystic fibrosis (CF) is the most common hereditary disease in Caucasians. Most of the patients are diagnosed at 2-3 years of age and treatment is focused on improving survival and quality of life and recommended to take place at a cystic fibrosis clinic where the lung, bowel and nutritional problems can be properly managed. Over the last three decades, improvement in treatment has increased life span to 40-50 years of age and cystic fibrosis-related diabetes (CFRD) has become the most common complication. A better understanding of the cellular and molecular mechanisms that result in CFRD will be fundamental for the improvement of diagnosis and treatment of this severe CF complication.