Drosophila Screens for Diabetes and Glucose Toxicity

描述（由申请人提供）：美国糖尿病协会估计，2002年II型糖尿病使美国人花费1320亿美元，使其和相关的代谢综合征成为我们社会中最广泛和最昂贵的代谢疾病。此外，目前估计到2010年全球糖尿病患者人数为2.5亿，其中94%表现为II型糖尿病。这些疾病的特征在于不能正确处理循环葡萄糖。在早期糖尿病中，患者表现出高血糖症和高胰岛素血症;疾病进展最终可导致胰腺β细胞和对循环葡萄糖适当反应的能力丧失。目前的治疗方法可以减缓疾病进展，但患者仍然面临血管问题、伤口愈合不良、周围神经病变、肾脏和肝脏功能障碍以及许多细胞和免疫应激相关问题的高风险。 本建议涉及两个核心问题。首先，并非所有的糖尿病患者都会因高血糖症而发生相同的并发症，这表明对葡萄糖毒性的易感性具有遗传成分。其次，目前的治疗方法对治疗这种疾病只有部分有效，需要新的治疗方法-包括药物治疗-来改善预后。 该提案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。通过给果蝇喂食高己糖的饮食，观察到了许多暗示人类代谢问题的缺陷。最值得注意的是一个强大的发育迟缓，已被证明是有用的筛选目的。最初的基因筛选已经暗示了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“高葡萄糖”果蝇对人类糖尿病患者常用的至少三种不同药物有反应，这表明该模型也可用于鉴定先导治疗化合物。用至少两种己糖筛选果蝇，以鉴定修饰发育迟缓表型的遗传基因座。此外，一种新的方法将被用来筛选苍蝇在一个高通量的方式，以确定新的先导治疗化合物。总之，这些遗传和化合物筛选应该提供重要的功能信息和新治疗的潜力。

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.