Selective cholecystokinin receptor signaling in the pancreatic islet as therapeutic target against diabetogenic stress

项目概要： 流行病学研究表明，在过去三十年中， 2型糖尿病患者的数量，从而导致无数糖尿病相关并发症， 相关死亡率。3000万糖尿病患者和8600万糖尿病患者每年给社会带来的额外经济成本 糖尿病前期患者估计为3220亿美元，占2010年医疗保健总支出的20%， 美国有更多的关于损失的收入和相关的不可估量的人类痛苦。2型 糖尿病由胰岛素抵抗增加和胰岛素产生减少引起。有一个 在糖尿病应激下适应性胰腺β细胞增殖的失败，以及细胞凋亡的增加， 减少β细胞的数量胆囊收缩素（cholesterostokinin，CCK）是一种由胰岛β细胞分泌的肠促胰岛素样激素 在压力和肥胖的情况下。缺乏CCK的肥胖小鼠胰岛具有减少的β细胞质量， 凋亡增加。在胰腺内分泌细胞中，我们已经证明CCK是必需的， 足以促进β-细胞存活并保护免于胡萝卜素介导的β-细胞死亡。但尽管 CCK在各种细胞类型和疾病模型中促存活作用的累积观察结果， β-细胞中的受体表达和活化大多是未知的。有必要了解哪些CCK 受体介导的促生存作用，在β细胞开发一种治疗，将利用 CCK在β细胞中的积极作用，在其他组织中具有最小量的脱靶副作用。很长的- 本提案的长期目标是鉴定和区分CCK信号通路的功能， 了解它们如何在糖尿病应激下对胰岛中的β细胞保护作用做出贡献， 确定特异性CCKR激动作用的治疗意义。为此，本提案旨在测试 核心假设是选择性调节β细胞中的CCK受体亚型特异性信号传导， 保护β细胞功能和质量。随着这一项目的完成，我们预计将更好地了解 选择性CCK激动剂的治疗潜力，这将为开发耐受性更好， 通过鉴定CCK信号传导的直接作用和机制， 促进β细胞存活。最后，该项目的完成将确保两个项目的成功进展。 研究和职业生涯的发展对我的博士生在分子和 细胞药理学，允许毕业生所需的素质和经验的平衡发展 我希望我的学生能够顺利地过渡到科学事业的下一个阶段，在那里我将继续进步 成为胰岛生物学领域的成功终身教授。

Project Summary: Epidemiological studies show that during the past three decades, there has been an alarming rate of growth in the number of type 2 diabetes patients, consequently driving the myriad diabetes-related complications and related mortality. The annual excess financial cost to society from 30 million diabetes patients and 86 million prediabetes patients is estimated to be $322 billion, a whopping 20% of the total health care spending in America with much more regarding lost revenue and associated immeasurable human suffering. Type 2 diabetes mellitus results from both increased insulin resistance and decreased insulin production. There is a failure of adaptive pancreatic β-cell proliferation under diabetic stress, as well as increased apoptosis leading to β-cell mass reduction. Cholecystokinin (CCK) is an incretin-like hormone produced by pancreatic β-cells under conditions of stress and obesity. Obese mouse islets lacking CCK have decreased β-cell mass and increased apoptosis. In pancreatic endocrine cells, we have demonstrated that CCK is both necessary and sufficient to promote β-cell survival and to protect from cytokine-mediated β-cell death. However, despite the accumulated observations of a pro-survival effect of CCK in various cell types and disease models, CCK receptor expression and activation in the β-cell is mostly unknown. There is a need to understand which CCK receptor mediates the pro-survival effects in the -cell to develop a therapeutic that will take advantage of the positive effects of CCK in the -cell with a minimal amount of off-target side effects in other tissues. The long- term goal of this proposal is to identify and distinguish the functions of the CCK signaling pathways, understand how they contribute to the β-cell protective effect in the pancreatic islet under diabetic stress, and determine the therapeutic significance of specific CCKR agonism. To that end, this proposal is aimed to test the central hypothesis that selective modulation of CCK receptor subtype-specific signaling in a beta-cell can protect β-cell function and mass. With the completion of this project, we anticipate to better understand the therapeutic potential of selective CCK agonist which will open new avenues of developing a better tolerated, target specific, and clinically relevant drug by identifying direct roles and mechanisms by which CCK signaling promotes β-cell survival. Finally, the completion of this project will ensure the successful progression of both research and professional career development towards the end of my doctoral training in molecular and cellular pharmacology, allowing a balanced development of qualities and experiences needed for a graduate student to make a smooth transition into the next stage of career in science where I will continue to progress towards becoming a successful, tenured professor in the field of islet biology.