Dynorphin, a novel paracrine factor that regulates insulin secretion

强啡肽，一种调节胰岛素分泌的新型旁分泌因子

• 批准号: 10658268
• 负责人: Manuel Blandino-Rosano
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-17 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658268
• 关键词: Beta Cell; Binding; Cell Communication; Cell physiology; Cell secretion; Cells; Communication; Complement; D Cells; Data; Diabetes Mellitus; Disease; Dynorphins; Epidemic; Exposure to; Family; Feedback; Genes; Genetic; Glucagon; Glucose; Goals; High Fat Diet; Hormonal; Hormone secretion; Hormones; Human; Hyperglycemia; Impairment; In Vitro; Incubated; Insulin; Insulin Resistance; Islet Cell; Islets of Langerhans; Knowledge; Life; Messenger RNA; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Opioid Antagonist; Opioid Peptide; Opioid Receptor; Outcome; Pain; Paracrine Communication; Pathologic; Phenotype; Physiological; Physiology; Public Health; Publishing; Regulation; Research; Role; Signal Transduction; Somatostatin; System; Testing; Therapeutic; Work; addiction; biological adaptation to stress; blood glucose regulation; cell injury; design; diabetes management; diabetogenic; endogenous opioids; experimental study; gamma-Aminobutyric Acid; glucose metabolism; improved; in vivo; innovation; insulin granule; insulin secretion; islet; kappa opioid receptors; mouse model; novel; novel strategies; overexpression; paracrine; pharmacologic; programs; response; therapeutic target; urocortin

Dynorphin, a novel paracrine factor that regulates insulin secretion The inability to maintain glucose homeostasis leads to diabetes, a life-threatening disease of epidemic proportions. The adaptation of pancreatic islets to insulin resistance is a significant determinant of developing type 2 diabetes (T2D). Within the pancreatic islet, the crosstalk between different islet cells through paracrine signals orchestrates a hormonal response that controls glucose levels. Dysregulation of these signals contributes to impaired glucose homeostasis and diabetes. The long-term goal of my research program is to understand how paracrine interactions within islet cells regulate hormone secretion and glucose homeostasis in physiological and pathological conditions. The objective of this proposal is to assess the β- to δ-cell Dynorphin (Dyn)/Kappa opioid receptor (KOR) negative feedback loop during physiology and pathological states. The central hypothesis is that insulin secretion is regulated by a novel β- to δ-cell Dyn/KOR negative feedback loop, and this feedback loop regulates glucose homeostasis and contributes to hyperglycemia in diabetes. The rationale underlying this proposal is that completion will identify key targets for improving insulin secretion in conditions of insulin resistance and diabetes. The central hypothesis will be tested by pursuing two specific aims: 1) Characterize the Dyn secretion in mouse and human β-cells and determine the contribution to islet function and glucose homeostasis (First component of the feedback loop). 2) Determine the role of δ-cell KOR and examine the potential of the Dyn/KOR axis as a therapeutic target in diabetes (Second component of the feedback loop). We will pursue these aims using an innovative combination of newly generated mice models with specific deletion of KOR in δ-cells and overexpression and deletion of Dyn in β-cells. The proposed research is significant because it will identify that the endogenous opioid peptide Dyn, is a key intra-islet paracrine molecule that regulates insulin secretion and glucose homeostasis. It is also significant because it will reveal how the regulation of KOR impacts islet secretion in diabetogenic conditions. This work will develop foundational knowledge of how Dyn and its function in islet cells impact glucose metabolism and insulin resistance. The proximate expected outcome of this work is understanding the mechanism of how the Dyn/KOR axis participates in the adaptation of β-cells to insulin resistance and β-cell injury. The results will have an important positive impact immediately. After all, we will uncover the role of the Dyn/KOR axis in islet function. Resolving the in vivo mechanisms of β- to δ-cell Dyn/KOR negative feedback loop will have profound implications for glucose homeostasis and serve to develop potential targets for T2D.

强啡肽：一种新的调节胰岛素分泌的旁分泌因子 无法维持葡萄糖稳态会导致糖尿病，这是一种危及生命的流行性疾病 比例。胰岛对胰岛素抵抗的适应性是胰腺癌发生的重要决定因素。 2型糖尿病（T2 D）。在胰岛内，不同胰岛细胞之间通过旁分泌的串扰 信号协调控制葡萄糖水平的激素反应。这些信号的失调有助于 葡萄糖稳态受损和糖尿病。 我的研究项目的长期目标是了解胰岛细胞内的旁分泌相互作用 在生理和病理条件下调节激素分泌和葡萄糖稳态。客观 该建议的一个目的是评估β-至δ-细胞强啡肽（Dyn）/κ阿片受体（KOR）的负反馈 在生理和病理状态下循环。核心假设是胰岛素分泌是由一种 新的β-至δ-细胞Dyn/KOR负反馈回路，该反馈回路调节葡萄糖稳态， 导致糖尿病的高血糖症。这项建议的基本理由是，完成这项工作将确定 在胰岛素抵抗和糖尿病条件下改善胰岛素分泌的关键目标。核心假设 将通过追求两个具体目标进行测试： 1)表征小鼠和人β细胞中的Dyn分泌，并确定对胰岛功能的贡献 和葡萄糖稳态（反馈回路的第一个组成部分）。 2)确定δ细胞KOR的作用，并检查Dyn/KOR轴作为治疗靶点的潜力， 糖尿病（反馈循环的第二个组成部分）。 我们将使用新产生的小鼠模型与特定的 δ-细胞中KOR的缺失和β-细胞中Dyn的过表达和缺失。 这项研究具有重要意义，因为它将确定内源性阿片肽Dyn是一个关键因素， 调节胰岛素分泌和葡萄糖稳态的胰岛内旁分泌分子。有着现实的指导意义 因为它将揭示在糖尿病发生条件下KOR的调节如何影响胰岛分泌。这项工作将 发展Dyn及其在胰岛细胞中的功能如何影响葡萄糖代谢和胰岛素的基础知识 阻力这项工作的最接近的预期成果是了解Dyn/KOR如何 轴参与β细胞对胰岛素抵抗和β细胞损伤的适应。 结果将立即产生重要的积极影响。毕竟，我们将揭示的作用， Dyn/KOR轴在胰岛功能中的作用解决β-到δ-细胞Dyn/KOR负反馈的体内机制 环将对葡萄糖稳态产生深远的影响，并有助于开发T2 D的潜在靶点。