The delta cell as a key regulator of pancreatic islet biology

δ细胞作为胰岛生物学的关键调节因子

• 批准号: 10178008
• 负责人: Rayner Rodriguez-Diaz
• 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: 2020
• 资助国家: 美国
• 起止时间: 2020-06-05 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10178008
• 关键词: Ablation; Address; Affect; Afferent Neurons; Alpha Cell; Back; Beta Cell; Biology; Cell physiology; Cells; Chronic; Communication; D Cells; Data; Development; Diabetes Mellitus; Electrophysiology (science); Elements; Endocrine; Endocrine Glands; Feedback; Feeds; Functional Imaging; Glucagon; Glucose; Goals; Homeostasis; Hormone Antagonists; Hormone secretion; Human; Immune; Immune response; Immune signaling; Immune system; Immunomodulators; In Vitro; Individual; Infiltration; Inflammation; Insulin; Islet Cell; Islets of Langerhans; Mediating; Membrane Potentials; Metabolic; Modeling; Mus; Natural History; Nervous system structure; Neurons; Neuropeptides; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pancreas; Pancreatic delta Cell; Paracrine Communication; Peptides; Pharmacology; Pilot Projects; Play; Positioning Attribute; Regulation; Research; Role; Signal Transduction; Slice; Somatostatin; Source; Stimulus; Substance P; System; Testing; Tissues; Work; afferent nerve; base; cell type; cytokine; diabetes pathogenesis; diabetic; diphtheria toxin receptor; gamma-Aminobutyric Acid; glucose metabolism; high body mass index; in vivo; insulin secretion; islet; mouse model; nerve supply; neuroinflammation; novel; optogenetics; paracrine; recruit; relating to nervous system; response; tool

ABSTRACT The delta cell of the pancreatic islet has been barely investigated despite secreting somatostatin (SST), a powerful inhibitory peptide that is essential for the homeostasis of different tissues. In the islet, SST inhibits the secretion of insulin and glucagon, but little is known about the mechanisms that activate delta cell and SST secretion. No other roles have been investigated or even proposed for the delta cell in islet biology and glucose metabolism. The nervous system, endocrine organs, and local neighboring cells, including immune cells, could potentially interact with the delta cell as a “switch” or “brake” to modulate the function of the whole islet. It is clear that the relevance of this powerful inhibitory component in the islet has been overlooked. The position of the delta cell as a key element in the regulation of islet hormone secretion needs to be addressed to understand how islet hormone secretion is regulated. The general hypothesis of this proposal is that the delta cell is a signaling hub where paracrine, immune and nervous signals converge and are integrated to set the level of SST secretion that ultimately modulates overall islet activity. This hypothesis will be tested through two related but not interdependent aims. In Aim 1 we will study the role of GABA as a key paracrine signal in delta cell function. Our previous results suggest that delta cell function is tightly adjusted by GABA, a paracrine signal secreted by beta cells through glucose independent mechanisms. GABA could therefore modulate delta cell responses to other local signals. We will use human islets and, when translatable, mouse islets to determine (1.1) the effects of endogenous GABA on the magnitude of basal SST secretion, (1.2) the effects of endogenous GABA on delta cell responses to glucose and other, local signals, and (1.3) how loss of endogenous GABA signaling contributes to the changes in somatostatin secretion in high BMI and type 2 diabetes. In Aim 2 we will examine the role of the delta cell and SST signaling in islet inflammation. Our preliminary findings indicate that the delta cell responds to signals from the immune and neural compartments and secretes SST to counteract inflammation and neuroinflammation. Thus, the delta cell could protect the islet from unchecked and damaging immune responses. We will test (2.1) the effects of cytokines and proinflammatory neuropeptides on delta cells, and (2.2) the effect of SST on local immune cells and sensory nerves. We will use a combination of novel in vitro (isolated islets), ex vivo (pancreatic tissue slices), and in vivo (intraocular islet grafts) approaches together with pharmacological tools, optogenetic stimulation, cell ablation, functional imaging and systemic metabolic readouts to study how delta cells are activated and how they influence the sensory nerves and surrounding endocrine and immune cells. We expect our studies to further our understanding of the circumstances under which the delta cell is recruited to influence endocrine and immune cells in the islet. If SST’s role as an immunomodulator is validated, it is likely that the delta cell will be reconsidered as a key element in the natural history of diabetes. Therefore, important advances in our understanding of the pathogenesis of diabetes could be expected.

摘要 尽管胰岛的δ细胞分泌生长抑素（SST）， 对不同组织的体内平衡至关重要的强大抑制肽。在胰岛中，SST抑制 分泌胰岛素和胰高血糖素，但对激活δ细胞和SST的机制知之甚少 分泌物没有其他的角色已经调查，甚至提出了在胰岛生物学和葡萄糖的δ细胞 新陈代谢.神经系统、内分泌器官和局部邻近细胞，包括免疫细胞， 潜在地作为“开关”或“制动器”与δ细胞相互作用以调节整个胰岛的功能。显然 胰岛中这种强有力的抑制成分的相关性被忽视了。的位置 δ细胞作为调节胰岛激素分泌的关键因素， 如何调节胰岛激素分泌。这个建议的一般假设是，三角洲细胞是一个 信号中枢，旁分泌、免疫和神经信号汇聚并整合以设定SST水平 最终调节整体胰岛活性的分泌。这一假设将通过两个相关的，但 而不是相互依赖的目标。在目标1中，我们将研究GABA作为δ细胞功能中的关键旁分泌信号的作用。 我们先前的研究结果表明，δ细胞的功能受到GABA的密切调节，GABA是一种由细胞分泌的旁分泌信号。 β细胞通过葡萄糖非依赖性机制。因此，GABA可以调节δ细胞对 其他本地信号我们将使用人类胰岛和小鼠胰岛（如果可以翻译）来确定（1.1）效应 内源性GABA对基础SST分泌量的影响;（1.2）内源性GABA对基础SST分泌量的影响 细胞对葡萄糖和其他局部信号的反应，以及（1.3）内源性GABA信号的丢失如何促成 高BMI和2型糖尿病患者生长抑素分泌的变化。在目标2中，我们将研究 胰岛炎症中的δ细胞和SST信号。我们的初步发现表明， 从免疫和神经隔室的信号和分泌SST，以抵消炎症， 神经炎症因此，δ细胞可以保护胰岛免受未经检查和破坏性免疫反应的影响。 我们将测试（2.1）细胞因子和促炎神经肽对δ细胞的影响，以及（2.2）细胞因子和促炎神经肽对δ细胞的影响。 SST对局部免疫细胞和感觉神经的影响。我们将使用新的体外（分离的胰岛）， 离体（胰腺组织切片）和体内（眼内胰岛移植物）方法与药理学方法一起 工具，光遗传学刺激，细胞消融，功能成像和全身代谢读数，以研究如何 δ细胞被激活，以及它们如何影响感觉神经和周围的内分泌和免疫 细胞我们希望我们的研究能进一步了解δ细胞在何种情况下生长， 募集来影响胰岛内的内分泌和免疫细胞。如果SST作为免疫调节剂的作用得到验证， δ细胞可能会被重新视为糖尿病自然史中的关键因素。因此，我们认为， 我们对糖尿病发病机理的理解有望取得重大进展。