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.

抽象的 尽管分泌生长抑素（SST），但胰腺中的三角洲细胞是 强大的抑制肽对于不同组织的稳态至关重要。 胰岛素和胰高血糖素的分泌，但对激活三角细胞和SST的机制知之甚少 分泌。 代谢 潜在地将Delta单元作为“开关”或“制动”相互作用，以模块化整个小岛的功能。 胰岛中的硫代分量的相关性已被忽略。 需要解决胰岛激素分泌调节的关键要素才能理解 胰岛激素分泌是常规的。 信号枢纽，旁分泌，免疫和神经信号会收敛并整合以设置SST的水平 分泌及时调节整体胰岛活动。 不是AIM 1中的互动目标。 我们先前的结果表明，Delta细胞功能是由GABA严格调整的，GABA是一个分泌的旁分泌信号 β细胞通过葡萄糖独立机制。 其他局部信号。 内源性GABA在基础SST秘密的大小上，内源性GABA对三角洲的影响 细胞对葡萄糖和其他局部信号的反应，以及（1.3）内源性GABA信号的损失如何促进 对于高BMI和2型糖尿病中的生长抑素分泌的变化。 Delta细胞和SST在胰岛炎症中持续信号传导。 来自免疫和神经室的信号，并分泌SST以抵消炎症和 因此，神经炎症。 我们将测试（2.1）细胞因子和促炎性神经肽对三角细胞的影响，以及（2.2）效果 SST在局部Imune细胞和感觉神经上。 离体（胰组织切片）和体内（眼内移植物）与药物一起接近 工具，光遗传刺激，细胞消融，功能成像和全身代谢读数，以研究如何 三角洲细胞被激活，以及它们如何影响感觉神经和异分分泌和分泌ammune 细胞。我们希望我们的研究能够进一步了解这种情况。 如果SST作为免疫调节剂的作用，请招募到胰岛中的免疫细胞 Delta细胞很可能会重新考虑为糖尿病自然史上的关键要素。 我们对糖尿病发病机理的理解的重要进展只能