Dynamics of Pancreatic Islet Function

胰岛功能的动态变化

• 批准号: 7535545
• 负责人: David W Piston
• 金额: $ 30.84万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7535545
• 关键词: Accounting; Action Potentials; Alleles; Alpha Cell; Behavior; Biochemical; Biological; Blood; Blood Glucose; Cell Communication; Cell membrane; Cells; Communication; Coupled; Coupling; Dominant-Negative Mutation; Event; Exhibits; Feedback; Fluorescence; Fluorescence Microscopy; Funding; Gap Junctions; Giant Cells; Glucagon; Glucose; Goals; Human; Image; Insulin; Insulin-Dependent Diabetes Mellitus; Investigation; Ions; Islets of Langerhans; Knock-in Mouse; Knock-out; Knockout Mice; Lead; Life; Measurement; Measures; Membrane; Membrane Potentials; Metabolic; Metabolism; Methods; Microfluidic Microchips; Modeling; Molecular; Motivation; Mus; Nature; Non-Insulin-Dependent Diabetes Mellitus; Paracrine Communication; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Relative (related person); Research; Role; Signal Transduction; Structure; Techniques; Testing; Time; Tissues; Transgenic Mice; Transgenic Organisms; Transplantation; Work; base; blood glucose regulation; cell type; gap junction channel; imaging modality; in vivo; insulin secretion; interstitial; islet; molecular dynamics; mouse model; novel; optical imaging; pancreatic islet function; paracrine; promoter; research study; response; success

The islet of Langerhans is the functional unit responsible for glucose-stimulated insulin secretion (GSIS), and thus plays a key role in blood glucose homeostasis. The importance of the islet is demonstrated by the proven ability of islet transplants to reverse Type I diabetes pathologies in human patients. Further, it has long been known that an islet yields -10 fold greater insulin response to glucose than an equivalent mass of isolated p-cells. The long-term goal of this project is to understand the multicellular mechanisms of islet function, and their role in the regulation of blood glucose under normal and pathological conditions. In many ways, the islet appears to function as a syncytium, which exhibits synchronous behavior of membrane action potentials, Ca2+ oscillations, and pulsatile insulin secretion across all p-cells in the islet. Despite the importance of the islet, we still have only a rudimentary understanding of the basic multicellular mechanisms that lead to these synchronous behaviors and to enhanced GSIS. The islet is also made up of different cell types, and very little is known about the interplay between the different cells. We hypothesize that gap junction coupling between fl cells in the islet leads to the synchronous behaviors, and this in turn, accounts for a majority of the increased insulin response from intact islets over isolated/?ce//s, although paracrine signaling between fi-cells and between the different cell types also plays a modulatory role. The validity and limits of this hypothesiswill be tested via three specific aims: 1) Determine the relative conductance strength of gap junction coupling between p-cells in terms of the KATP channel conductance; 2) Determine the role of intra- and intercellular metabolism in the glucose-stimulated Ca2+ oscillations in p-cells within intact islets; and 3) Determine the metabolic, membrane potential, and Ca2+ dynamic changes of the a-cell in response to glucose, and the influences of p-cell activity on these responses. Using our unique quantitative optical imaging methods and novel microfluidic devices, the dynamics of these molecular mechanisms can be followed quantitatively in living cells within intact islets. These investigations will also utilize several available transgenic and tissue-specific knock-out mouse models with demonstrated phenotypes, as well as traditional biochemical and molecular biological approaches. Lay Summary: We propose to study the function of pancreatic islets, which contain the insulin-secreting p- cells. Two health-related motivations underlie the proposed work. First, a better understanding of pancreatic islet function is necessary to increase the success rate of islet transplants, which are a promising strategy to cure Type I diabetes. Second, understanding the cell-to-cell communication pathways may lead to new drugs that enhance insulin secretion for the treatment of Type II diabetes.

Langerhans的胰岛是负责葡萄糖刺激的胰岛素分泌（GSIS）的功能单元，并且 因此，在血糖稳态中起关键作用。胰岛的重要性由 胰岛移植能够反向人类患者逆转I型糖尿病病理的能力。此外，它还有 长期以来，胰岛产生-10倍的胰岛素对葡萄糖的反应大于等效质量的胰岛素反应 孤立的P细胞。该项目的长期目标是了解胰岛的多细胞机制 功能及其在正常和病理条件下的血糖调节中的作用。许多人 方式，胰岛似乎起着合成剂的作用，它表现出膜作用的同步行为 胰岛所有P细胞的电势，Ca2+振荡和脉冲胰岛素分泌。尽管有 胰岛的重要性，我们仍然对基本多细胞机制有基本的理解 这导致了这些同步行为并增强了GSI。胰岛也由不同的单元组成 对于不同细胞之间的相互作用，类型几乎没有知识。我们假设这个差距 胰岛中FL单元之间的连接耦合导致同步行为，这反过来又有帐户 对于大多数胰岛素的胰岛素反应增加而不是孤立的胰岛//c // s，尽管旁分泌 FI细胞和不同细胞类型之间的信号传导也起着调节作用。有效性和 该假设的限制将通过三个特定目的测试：1）确定相对电导强度 P-Cells之间的间隙连接耦合在KATP通道电导方面； 2）确定 完整胰岛内的P细胞中葡萄糖刺激的Ca2+振荡中的细胞内代谢； 3）确定A细胞的代谢，膜电位和Ca2+动态变化。 葡萄糖以及P细胞活性对这些反应的影响。使用我们独特的定量光学 成像方法和新型微流体设备，这些分子机制的动力学可以是 在完整胰岛内的活细胞中进行定量。这些调查还将利用几个可用的 具有证明表型的转基因和组织特异性敲除小鼠模型以及传统 生化和分子生物学方法。 摘要：我们建议研究胰岛的功能，其中包含分泌胰岛素的P- 细胞。拟议工作的两个与健康有关的动机是基于拟议工作的。首先，更好地了解胰腺 胰岛功能对于提高胰岛移植的成功率是必要的，这是一个有希望的策略 治愈I型糖尿病。其次，了解细胞到细胞的通信途径可能会导致新 增强胰岛素分泌的药物用于治疗II型糖尿病。