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

胰岛中选择性胆囊收缩素受体信号传导作为抗糖尿病应激的治疗靶点

• 批准号: 9922665
• 负责人: HyungTae Kim
• 金额: $ 4.55万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922665
• 关键词: Address; Adverse effects; Agonist; Americas; Apoptosis; Apoptotic; Attenuated; Automobile Driving; B Cell Proliferation; Beta Cell; Biology; CCKBR gene; CREB1 gene; Cell Death; Cell Survival; Cell physiology; Cells; Cholecystokinin; Cholecystokinin Receptor; Clinical; Complications of Diabetes Mellitus; Coupled; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Development; Diabetes Mellitus; Diabetes prevention; Diabetic mouse; Disease model; Drug Targeting; Ensure; Epidemic; Exocrine pancreas; Exposure to; Failure; Financial cost; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Growth; Healthcare; Hormones; Human; In Vitro; Insulin; Insulin Resistance; Investigation; Islets of Langerhans; Islets of Langerhans Transplantation; Mammalian Cell; Mediating; Molecular; Mus; Neuraxis; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Outcome; Pancreas; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Population; Prediabetes syndrome; Prevalence; Production; Receptor Activation; Receptor Signaling; Research; Role; Science; Signal Pathway; Signal Transduction; Societies; Stress; Structure of beta Cell of islet; Testing; Therapeutic; Therapeutic Agents; Tissues; Training; Translations; base; career; career development; cell type; clinically relevant; cytokine; diabetes mellitus therapy; diabetes pathogenesis; diabetic; diabetogenic; epidemiology study; experience; functional decline; gastrointestinal system; graduate student; improved; in vivo; islet; mortality; novel strategies; overexpression; prevent; professor; protective effect; receptor; receptor expression; side effect; stressor; therapeutic target; therapy development

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.

项目概要： 流行病学研究表明，在过去三十年里，该病的增长速度令人震惊。 2 型糖尿病患者的数量，从而导致了无数与糖尿病相关的并发症， 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超额经济成本 糖尿病前期患者估计花费 3,220 亿美元，占医疗保健总支出的 20% 美国的收入损失和与之相关的无法估量的人类苦难要严重得多。 2型 糖尿病是由胰岛素抵抗增加和胰岛素产生减少引起的。有一个 糖尿病应激下适应性胰腺 β 细胞增殖失败以及细胞凋亡增加导致 β细胞质量减少。胆囊收缩素 (CCK) 是一种由胰腺 β 细胞产生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β细胞质量减少 细胞凋亡增加。在胰腺内分泌细胞中，我们已经证明CCK既是必需的，也是 足以促进 β 细胞存活并防止细胞因子介导的 β 细胞死亡。然而，尽管 累积观察 CCK 在各种细胞类型和疾病模型中的促生存作用，CCK β细胞中受体的表达和激活大多是未知的。需要了解哪个CCK 受体介导  细胞中的促生存效应，以开发一种治疗方法，该疗法将利用 CCK 在  细胞中产生积极作用，而在其他组织中产生的脱靶副作用极小。长- 该提案的长期目标是识别和区分 CCK 信号通路的功能， 了解它们如何在糖尿病应激下对胰岛的 β 细胞保护作用做出贡献，以及 确定特异性 CCKR 激动的治疗意义。为此，本提案旨在测试 中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可以 保护β细胞功能和质量。随着这个项目的完成，我们希望能够更好地了解 选择性 CCK 激动剂的治疗潜力，这将为开发更好的耐受性、 通过识别 CCK 信号传导的直接作用和机制，靶向特定的、临床相关的药物 促进β细胞存活。最后，该项目的完成将确保双方的成功推进 在分子和分子生物学博士培训结束时进行研究和职业生涯发展 细胞药理学，使毕业生所需的素质和经验得到平衡发展 学生顺利过渡到科学职业的下一阶段，我将继续进步 成为胰岛生物学领域成功的终身教授。