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.

Dynorphin，一种调节胰岛素分泌的新型旁分泌因子 无法维持葡萄糖稳态导致糖尿病，这是一种威胁生命的流行病 胰岛对胰岛素抵抗的适应是发展的重要决定者 2型糖尿病（T2D）。在胰岛中，通过旁分泌之间的不同胰岛细胞之间的串扰 信号策划了控制葡萄糖水平的马响应。这些信号的失调有助于 葡萄糖稳态和糖尿病受损。 我的研究计划的长期目标是了解胰岛细胞中的旁分泌相互作用如何 在身体和病理状况下调节骑马分泌和葡萄糖稳态。目标 该建议的是评估β-至δ细胞大啡肽（DYN）/KAPPA阿片受体（KOR）负反馈 生理和病理状态期间的循环。中心假设是胰岛素分泌受A的调节 新型的β-至δ-cell dyn/kor负反馈回路，此反馈回路调节葡萄糖稳态和 导致糖尿病高血糖。该提议的基本原理是完成将确定 在胰岛素抵抗和糖尿病疾病中改善胰岛素分泌的主要靶标。中心假设 将通过追求两个具体目标来测试： 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（反馈循环的第一部分）。 2）确定δ-Cell Kor的作用，并检查Dyn/Kor轴作为治疗靶标的潜力 糖尿病（反馈循环的第二个组成部分）。 我们将使用新生成的小鼠模型的创新组合来追求这些目标 在δ细胞中删除kor，β细胞中DYN的过表达和缺失。 拟议的研究很重要，因为它将确定内源性阿片类药物的dyn是关键 调节胰岛素分泌和葡萄糖稳态的钟细胞内钟细胞核分子。这也很重要 因为它将揭示如何在糖尿病生成条件下对胰岛分泌的调节。这项工作将 开发基础知识及其在胰岛细胞中的功能如何影响葡萄糖代谢和胰岛素 反抗。这项工作的最直接的预期结果是了解Dyn/Kor的机制 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，我们将发现 胰岛功能中的dyn/kor轴。解决β-到δ细胞dyn/kor负反馈的体内机制 循环将对葡萄糖稳态产生深远的影响，并为T2D开发潜在的靶标。