alpha-Endosulfine, Insulin,& Adult Tissue Growth Control

α-硫磺、胰岛素、

• 批准号: 7035768
• 负责人: Daniela Drummond-Barbosa
• 金额: $ 32.47万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035768
• 关键词: Drosophilidae; biological models; brain; cell growth regulation; cell proliferation; egg /ovum; enzyme activity; genetically modified animals; hemolymph; hormone regulation /control mechanism; insulin; insulinlike growth factor; nutrition; oogenesis; ovary; pancreatic islet function; phosphoproteins; phosphorylation; potassium channel; protein kinase A; protein protein interaction; protein quantitation /detection; tissue /cell culture

DESCRIPTION (provided by applicant): Little is known about how adult tissues maintained by stem cells sense and respond to external stimuli such as changes in nutrition. We established the Drosophila ovary as a model system in which to study this question. We showed that nutritional status can control the number of cells produced in the Drosophila ovary, and that the insulin pathway and alpha-endosulfine are part of the regulatory machinery. In mammals, alpha-endosulfine is likely to be involved in the regulation of ion channels and in the secretion of insulin; however, the available evidence as to its precise role is conflicting. In pancreatic beta cells in culture, alpha-endosulfine binds to the regulatory subunit, SUR, of a potassium channel, triggering membrane depolarization, calcium influx and secretion of insulin. In other studies, alpha-endosulfine was shown to inhibit insulin secretion by blocking calcium channels. Genetic analyses, which will be crucial in resolving the current controversies and understanding the in vivo role of alpha-endosulfine, have not yet been conducted. We propose a focused set of genetic approaches, combined with biochemical and cell biological assays, to address the role of alpha-endosulfine in tissue growth regulation, and test the hypothesis that it regulates ion channel activity and insulin secretion in vivo. The specific aims are: (1) to determine in what tissue alpha-endosulfine is required and if it is involved in insulin secretion; (2) to determine if alpha-endosulfine acts via the modulation SUR activity; and (3) to investigate the mechanism of regulation of alpha-endosulfine. These approaches will contribute significantly to the understanding of the role of alpha-endosulfine in insulin secretion, as well as of normal biological processes in which insulin is required. In particular, they will help elucidate mechanisms that lead to type n diabetes, an important step towards the development of new drugs to treat this disease. In addition, these studies will provide new insights into how stem cell-supported tissues respond to nutritional changes and, perhaps, identify new ways to manipulate this response for therapeutic purposes.

描述（由申请人提供）：关于干细胞维持的成体组织如何感知和响应外部刺激（例如营养变化），人们知之甚少。我们建立了果蝇卵巢作为研究这个问题的模型系统。我们表明，营养状况可以控制果蝇卵巢中产生的细胞数量，并且胰岛素途径和α-硫辛是调节机制的一部分。在哺乳动物中，α-硫磺可能参与离子通道的调节和胰岛素的分泌。然而，关于其确切作用的现有证据是相互矛盾的。在培养的胰腺β细胞中，α-硫磺与钾通道的调节亚基SUR结合，引发膜去极化、钙内流和胰岛素分泌。在其他研究中，α-硫磺被证明可以通过阻断钙通道来抑制胰岛素分泌。遗传分析对于解决当前争议和理解α-硫辛的体内作用至关重要，但尚未进行。我们提出了一套集中的遗传方法，结合生化和细胞生物学测定，以解决α-硫磺在组织生长调节中的作用，并测试它在体内调节离子通道活性和胰岛素分泌的假设。具体目标是：（1）确定哪些组织需要α-硫丹以及它是否参与胰岛素分泌； (2) 确定α-硫磺是否通过调节SUR活性起作用； (3)研究α-硫磺的调节机制。这些方法将极大地有助于了解α-硫磺在胰岛素分泌中的作用，以及需要胰岛素的正常生物过程。特别是，它们将有助于阐明导致 n 型糖尿病的机制，这是开发治疗这种疾病的新药的重要一步。此外，这些研究将为干细胞支持的组织如何响应营养变化提供新的见解，并可能确定操纵这种响应以达到治疗目的的新方法。