SPECIFIC INHIBITORS OF PREADIPOCYTE REPLICATION

肥胖是一个公认的风险因素，许多疾病，包括2型糖尿病和冠心病。虽然减肥是2型糖尿病最有效的治疗方法，但目前的减肥方法通常不足以长期减肥。AdipoGenix公司的使命是发现，开发和许可在脂肪细胞水平作用的新疗法，用于治疗肥胖和相关疾病。肥胖是脂肪细胞增大和脂肪细胞数量增加的结果。前脂肪细胞是脂肪组织中能够复制或分化成脂肪细胞的前体细胞。脂肪组织中前脂肪细胞数量的减少导致体重下降。我们建议开发一个高通量的初步筛选，以确定特定的前脂肪细胞复制抑制剂。此外，我们将设计利用各种细胞类型的二次筛选，以表征在初步筛选中鉴定的活性化合物的细胞类型特异性。重要的是，原代细胞将用于这些测定，因为过去已经显示几种其他试剂如激素和旁分泌因子不同地影响整倍体原代细胞和非整倍体细胞系。此外，我们将进一步表征我们已经确定的啮齿动物和人类前脂肪细胞复制的独特抑制剂。 这种热稳定的低分子量抑制剂以年龄依赖性方式从啮齿动物前脂肪细胞产生。 我们将扩大这种抑制剂的生产并表征其结构。 通过这些努力确定的特异性抑制剂有望导致新型有效减肥药物的开发。建议的商业应用：在美国，肥胖症每年在直接和间接卫生保健费用方面使国民经济损失超过700亿美元。尽管有明显的医疗需求，但现有的市售药物对减肥效果甚微。对前脂肪细胞复制抑制剂的分析将导致发现新的化合物来专门对抗肥胖，这将具有巨大的市场潜力。

Obesity is a well-established risk factor for a number of diseases, including type 2 diabetes and coronary heart disease. While weight loss is the most effective treatment of type 2 diabetes, current methods for reducing weight are typically insufficient for long-term weight loss. The mission of AdipoGenix, Inc. is to discover, develop, and license novel therapeutics acting at the level of the fat cell for the treatment of obesity and related disorders. Obesity is a result of both fat cell enlargement and an increase in fat cell number. Preadipocytes are precursor cells in fat tissue capable of replicating or differentiating into fat cells. A decrease in the number of preadipocytes in fat tissue results in a decrease in body weight. We propose to develop a high-throughput primary screen to identify specific inhibitors of preadipocyte replication. Furthermore, we will devise secondary screens utilizing various cell types to characterize the cell-type specificity of active compounds identified in the primary screen. Importantly, primary cells will be used in these assays, since several other agents such as hormones and paracrine factors have been shown in the past to affect euploid primary cells and aneuploid cell lines differently. In addition, we will further characterize a unique inhibitor of rodent and human preadipocyte replication that we have identified. This heat stable, low molecular weight inhibitor is produced in an age-dependent manner from rodent preadipocytes. We will scale up production of this inhibitor and characterize its structure. Specific inhibitors identified through these efforts are expected to lead to development of novel, effective drugs for weight loss. PROPOSED COMMERCIAL APPLICATIONS: In the U.S., obesity costs the national economy more than $70 billion annually in both direct and indirect health care costs. Despite the obvious medical need, existing marketed drugs are marginally effective toward weight loss. Assays for inhibitors of preadipocyte replication will lead to the discovery of novel compounds to combat obesity specifically and that will have significant market potential.