alpha-Endosulfine, Insulin,& Adult Tissue Growth Control

描述（由申请人提供）：对于干细胞维持的成体组织如何感知和响应外部刺激（如营养变化）知之甚少。我们建立了果蝇卵巢作为模型系统来研究这个问题。我们发现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 -亚砜是调节机制的一部分。在哺乳动物中，α -亚砜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 -亚砜与钾通道的调节亚基SUR结合，触发膜去极化、钙内流和胰岛素分泌。在其他研究中，α -亚砜被证明通过阻断钙通道抑制胰岛素分泌。遗传分析对于解决目前的争议和了解α -亚砜在体内的作用至关重要，但尚未进行。我们提出了一套重点的遗传方法，结合生化和细胞生物学分析，来解决-亚砜在组织生长调节中的作用，并验证它在体内调节离子通道活性和胰岛素分泌的假设。具体目的是：(1)确定哪些组织需要α -亚砜，以及它是否参与胰岛素分泌；(2)确定α -亚砜是否通过调节SUR活性起作用；(3)研究α -亚砜的调控机制。这些方法将有助于理解α -亚砜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对营养变化作出反应提供新的见解，并可能为治疗目的确定操纵这种反应的新方法。

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.