Mechanisms of Somatostatin-Mediated Inhibition of Insulin and Glucagon

生长抑素介导的胰岛素和胰高血糖素抑制机制

基本信息

批准号：
10537377
负责人：
Ryan Hart
金额：
$ 3.92万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10537377
关键词：
Actins Address Adenosine Monophosphate Affect Agonist Alpha Cell American Americas Attenuated Automobile Driving Beta Cell Calcium Cell surface Cells Cilia Complement Complex Coupled Cyclic AMP D Cells Data Diabetes Mellitus Endocrine System Diseases Exocytosis F-Actin Family Functional Imaging GTP-Binding Proteins Genetic Transcription Glucagon Glucose Guanosine Triphosphate Phosphohydrolases Hormone secretion Hormones Hypoglycemia Image Individual Insulin Insulin-Dependent Diabetes Mellitus Islet Cell Islets of Langerhans Kinetics Knowledge Lead Mechanics Mediating Metabolic Mission Molecular Monomeric GTP-Binding Proteins Mus National Institute of Diabetes and Digestive and Kidney Diseases Non-Insulin-Dependent Diabetes Mellitus Outcome Paracrine Communication Periodicity Pharmacology Population Public Health Quality of life Receptor Activation Reporter Research Resolution Role SSTR2 gene SSTR3 gene Secretory Vesicles Signal Transduction Somatostatin Somatostatin Receptor Specificity Structure of beta Cell of islet Testing Time Tissues Transgenic Mice United States Weight antagonist attenuation base cell type experimental study imaging approach improved innovation insulin secretion islet live cell imaging next generation sequencing novel peptide hormone polymerization receptor response rho selective expression sensor somatostatin receptor 1 spatiotemporal targeted treatment transcriptome transcriptomics type I and type II diabetes

项目摘要

Somatostatin (SST) is a major inhibitory hormone that is capable of attenuating both glucagon and insulin secretion from alpha (α) and beta (β) cells respectively within the pancreatic islet of Langerhans. However, there is a critical gap in our understanding of the basic signaling mechanisms downstream of Somatostatin Receptor (SSTR) activation, and how these favor the inhibition of insulin secretion under some circumstances and the inhibition of glucagon secretion under others. Through transcriptomic analysis of purified α and β cell populations I have identified key differences and potential similarities between both which may begin to explain their cell specific SST response. Central to these observations, the SSTR profile which provides the input signal between either cell type is fundamentally different between α and β cells, with both cell types expressing SSTR3 on primary cilia, while α cells additionally express SSTR2 on their cell surface. Somatostatin signaling is typically suggested to lead to the inhibition of calcium and/or cAMP in the islet, but the relative importance of SST’s effect on these parallel signaling cascades is not understood. Furthermore, I have identified a novel SSTR mediated effector mechanism that actively drives the remodeling of filamentous actin (F-actin) with implications for secretory granule exocytosis. As such, my central hypothesis is that selective activation of SSTR3 on β cells and SSTR2 or SSTR3 on α cells will attenuate insulin and glucagon secretion via distinct effects on the quality and kinetics of Ca2+ and cAMP responses and downstream F-actin polymerization. I will pursue this hypothesis through two separate aims anchored by high throughput functional imaging of intact islets. First, I will leverage transgenic mouse lines in which fluorescent reporters of secondary messengers will be delivered to strictly α or β cells. These islets will then be subjected to individual SSTR agonists and antagonists to understand the individual contributions of identified cell specific SSTRs. Second, fluorescent reporters of F-actin dynamics will be employed in live imaging experiments to functionally determine the contribution of SSTR activation on F-actin polymerization and remodeling. These results will be coupled next generation sequencing data of purified populations of α and β cells treated with SST and SSTR type specific antagonists. The results of this aim will characterize an underlying F-actin response to SST contributing to overall hormone attenuation. These approaches are innovative as they leverage the power of high throughput functional imaging of large populations of cells to characterize both a novel mechanism and cell type specific response in high resolution. Collectively, the results of these aims are significant as they will result in a more complete understanding of the mechanisms by which SST succeeds in attenuating insulin and glucagon release under different metabolic conditions. This understanding carries significant weight in developing cell specific SSTR agonists aimed at attenuating specific cell populations, with implications in targeted treatment of type I and II diabetes affecting over 30 million individuals in the United States of America.

生长抑素 (SST) 是一种主要的抑制激素，能够减弱胰高血糖素和胰岛素的作用然而，朗格汉斯胰岛内的α（α）和β（β）细胞分别分泌。是我们对生长抑素受体下游基本信号机制理解的一个关键差距（SSTR）激活，以及这些在某些情况下如何有利于抑制胰岛素分泌以及通过对纯化的 α 和 β 细胞群进行转录组分析，抑制其他条件下的胰高血糖素分泌。我已经确定了两者之间的关键差异和潜在相似之处，这可能开始解释它们的细胞特定的 SST 响应是这些观测的核心，SSTR 曲线提供了之间的输入信号。 α 细胞和 β 细胞之间的任何一种细胞类型都有根本的不同，这两种细胞类型都表达 SSTR3 初级纤毛，而 α 细胞通常在其细胞表面表达 SSTR2。建议导致胰岛中钙和/或 cAMP 的抑制，但 SST 作用的相对重要性此外，我还发现了一种新的 SSTR 介导的信号通路。主动驱动丝状肌动蛋白（F-肌动蛋白）重塑的效应机制，对因此，我的中心假设是 SSTR3 对 β 细胞的选择性激活。 α 细胞上的 SSTR2 或 SSTR3 将通过对质量的不同影响来减弱胰岛素和胰高血糖素的分泌以及 Ca2+ 和 cAMP 反应以及下游 F-肌动蛋白聚合的动力学我将继续研究这一假设。首先，我将利用完整胰岛的高通量功能成像来实现两个不同的目标。转基因小鼠品系，其中第二信使的荧光产生者将被严格传递到α或然后将这些胰岛置于单独的 SSTR 激动剂和拮抗剂中以了解其作用。其次，F-肌动蛋白动态的荧光产生者将被确定的细胞特异性 SSTR 的个体贡献。用于实时成像实验，从功能上确定 SSTR 激活对 F-肌动蛋白的贡献这些结果将与纯化的下一代测序数据相结合。用 SST 和 SSTR 类型特异性拮抗剂处理的 α 和 β 细胞群，该目标的结果将。描述了 F-肌动蛋白对 SST 的潜在反应，导致整体激素减弱。这些方法具有创新性，因为它们利用了大量人群的高通量功能成像的力量细胞以高分辨率共同表征新机制和细胞类型特异性反应。这些目标的结果意义重大，因为它们将使人们更全面地了解这些机制 SST 成功地减少了不同代谢条件下胰岛素和胰高血糖素的释放。了解对于开发旨在减弱特定细胞特异性 SSTR 激动剂的重要性细胞群，对影响超过 3000 万人的 I 型和 II 型糖尿病的靶向治疗具有影响美利坚合众国的个人。