SPECIFIC INHIBITORS OF PREADIPOCYTE REPLICATION

肥胖是许多疾病的公认风险因素，包括2型糖尿病和冠心病。虽然减肥是治疗2型糖尿病最有效的方法，但目前的减肥方法通常不足以实现长期减肥。AdipoGenix，Inc.的使命是发现、开发和批准在脂肪细胞水平上作用的治疗肥胖和相关疾病的新疗法。肥胖既是脂肪细胞增大的结果，也是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为脂肪细胞的前体细胞。脂肪组织中前脂肪细胞数量的减少会导致体重减轻。我们建议建立一种高通量的初步筛选来鉴定前脂肪细胞复制的特定抑制物。此外，我们将利用不同的细胞类型设计二次筛选，以表征在第一次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检测，因为过去已经证明，激素和旁分泌因子等其他几种因素对整倍体原代细胞和非整倍体细胞系的影响是不同的。此外，我们还将进一步鉴定我们已确定的一种独特的啮齿动物和人类前脂肪细胞复制抑制因子。这种耐热的低分子抑制物是由啮齿动物前脂肪细胞以年龄相关的方式产生的。我们将扩大这种抑制剂的生产，并对其结构进行表征。通过这些努力确定的特定抑制剂有望导致新的、有效的减肥药物的开发。拟议的商业应用：在美国，肥胖症每年给国民经济造成的直接和间接医疗成本都超过700亿美元。尽管有明显的医疗需求，但现有的市场药物对减肥几乎没有效果。对前体脂肪细胞复制抑制物的检测将导致发现专门对抗肥胖的新化合物，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.