alpha-Endosulfine, Insulin,& Adult Tissue Growth Control

α-硫磺、胰岛素、

• 批准号: 6917718
• 负责人: Daniela Drummond-Barbosa
• 金额: $ 27.33万
• 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/6917718
• 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）：关于干细胞的成年组织如何感知并响应外部刺激，例如营养变化，知之甚少。我们将果蝇卵巢建立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-内硫硫次是调节机制的一部分。在哺乳动物中，α-内硫硫碱可能参与离子通道的调节和胰岛素的分泌。但是，关于其确切作用的可用证据是冲突。在培养的胰腺β细胞中，α-内硫硫次与钾通道的调节亚基SUR结合，触发膜去极化，胰岛素的钙涌入和分泌胰岛素。在其他研究中，显示α-内硫硫次可以通过阻断钙通道抑制胰岛素的分泌。遗传分析对于解决当前的争议至关重要，并了解α-内硫硫胺的体内作用至关重要。我们提出了一组集中的遗传方法，结合生化和细胞生物学测定，以解决α-依磺酰丁在组织生长调节中的作用，并检验其调节离子通道活性和体内胰岛素分泌的假设。具体目的是：（1）确定需要在哪种组织α-内硫硫胺中以及是否参与胰岛素分泌； （2）确定α-内硫硫次是否通过调制SUR活性起作用； （3）调查α-硫硫胺调节的机理。这些方法将有助于理解α-内磺氨基硫酸盐在胰岛素分泌中的作用，以及需要胰岛素的正常生物学过程。特别是，它们将有助于阐明导致N型糖尿病的机制，这是朝着开发新药治疗这种疾病的重要一步。此外，这些研究将提供有关干细胞支撑组织如何应对营养变化的新见解，并可能确定以治疗目的操纵这种反应的新方法。