Drosophila Screens for Diabetes and Glucose Toxicity

描述(申请人提供)：美国糖尿病协会估计，II型糖尿病在2002年给美国人造成了1320亿美元的损失，使其和相关的代谢综合征成为我们社会中最普遍和代价最高的代谢性疾病。此外，目前的估计显示，到2010年，全球糖尿病患者人数将达到2.5亿人，其中94%的人患有II型糖尿病。这些疾病的特点是无法正确处理循环中的葡萄糖。在糖尿病早期，患者表现为高血糖和高胰岛素血症；疾病进展最终会导致胰腺β细胞和对循环葡萄糖做出适当反应的能力丧失。目前的治疗方法可以减缓疾病的进展，但患者仍然面临血管问题、伤口愈合不良、周围神经疾病、肾和肝脏功能障碍以及一系列与细胞和免疫应激相关的问题的高风险。 这项提案涉及两个核心问题。首先，并不是所有的糖尿病患者都会出现相同的高血糖并发症，这表明对葡萄糖毒性的易感性有遗传因素。其次，目前的治疗方法在治疗这种疾病方面只有部分效果，需要新的治疗方法--包括药物疗法--来改善预后。 这项提议提出了一种新的方法来识别新的基因和先导化合物来解决这些问题。通过给果蝇黑腹果蝇喂食高己糖饮食，观察到了一些缺陷，这些缺陷暗示着人类的新陈代谢问题。最值得注意的是强烈的发育延迟，事实证明，这对筛查目的很有用。最初的基因筛查已经涉及到已经与糖尿病和葡萄糖毒性有关的途径，包括代谢和应激途径。此外，这些高血糖果蝇至少对人类糖尿病患者常用的三种不同药物有反应，这表明该模型也可以用于识别铅治疗化合物。将用至少两种己糖对果蝇进行筛查，以确定修改发育延迟表型的遗传位点。此外，将利用一种新的方法以高通量的方式对苍蝇进行筛查，以确定新的铅治疗化合物。总之，这些基因和复合筛查应该提供重要的功能信息和新治疗的可能性。

DESCRIPTION (provided by applicant): The American Diabetes Association estimates that Type II diabetes mellitus cost Americans $132 billion in 2002, making it and related metabolic syndrome the most widespread and costly metabolic diseases in our society. Furthermore, current estimates place the number of people with diabetes at 250 million worldwide by 2010, with 94% exhibiting Type II. These diseases are characterized by the inability to properly process circulating glucose. In early stage diabetes, patients exhibit hyperglycemia and hyperinsulinemia; disease progression can eventually lead to loss of both pancreatic beta cells and the ability to respond appropriately to circulating glucose. Current treatments can slow disease progression, but patients are still at high risk for vascular problems, poor wound healing, peripheral neuropathies, kidney and liver malfunctions, and a host of cellular- and immune-stress related problems. Two central issues are addressed in this proposal. First, not all diabetic patients develop the same sets of complications from hyperglycemia, indicating that the susceptibility to glucose toxicity has a genetic component. Second, current treatments are only partially effective in treating the disease, and new therapies -- including drug therapies -- will be required to improve prognosis. This Proposal presents a novel approach for identifying new genes and lead compounds to address these issues. By feeding a diet high in hexose sugars to the fruitfly Drosophila melanogaster, a number of defects were observed that are suggestive of metabolic problems in humans. Most notable is a robust developmental delay that has proven useful for screening purposes. Initial genetic screens have implicated pathways already linked to diabetes and glucose toxicity, including metabolic and stress pathways. Further, these 'high-glucose' flies respond to at least three different drugs that are commonly utilized in human diabetic patients, indicating that this model can also be useful for identifying lead therapeutic compounds. Flies will be screened with at least two hexose sugars to identify genetic loci that modify the developmental delay phenotype. Further, a novel approach will be utilized to screen flies in a high-throughput manner to identify new lead therapeutic compounds. Together, these genetic and compound screens should provide important functional information and the potential for new treatments.