VALIDATION OF HMGI-C AS A DRUG TARGET IN OBESITY

HMgene治疗肥胖症的独特、新颖的方法是开发直接作用于脂肪组织的药物。第二阶段的目标将是进一步验证HMGI-C作为肥胖症的药物靶点。HMGI-C是一种结构性转录因子，在脂肪形成过程中调节基因表达。在第一阶段，研究表明，HMGI-C的失活逆转了瘦素缺乏导致的肥胖。第二阶段将扩展这些研究，以表明同样适用于饮食诱导的肥胖症，这是一种更具生理学的模型，与人类疾病更相似。由于HMGI-C是一种转录调节因子，位于基因组级联的顶端，DNA微阵列和RNA差异显示技术将被用于识别HMGI-C基因组途径中的基因，这将提供新的药物靶点。最后，由于最终目标是开发一种安全、有效的治疗肥胖症的方法，将开发基于生化和细胞的检测方法，以筛选可能在肥胖症治疗中有用的HMGI-C小分子抑制剂。拟议的商业应用：该项目的成功完成将为发现有效的、具有临床价值的减肥药物开辟新的前景，这将具有巨大的商业潜力。据估计，一种处方药在美国的年销售额约为10亿美元。对于非处方药，潜在市场据信为100亿美元。

The unique, novel approach of HMGene to obesity treatment is to develop drugs that act directly on adipose tissue. The goal of Phase II will be to further validate HMGI-C, an architectural transcription factor which regulates gene expression in adipogenesis, as a drug target in obesity. In Phase I, it was shown that inactivation of HMGI-C reverses the obesity induced by leptin deficiency. Phase II will extend those studies to show that the same holds true for diet induced obesity which is a more physiological model and more closely parallels the human disease. As HMGI-C is a transcriptional regulator and sits at the apex of a genomic cascade, DNA microarray and RNA differential display technology will be used to identify genes in the HMGI-C genomic pathway which will provide novel drug targets. Finally, as the ultimate goal is to develop a safe, effective therapeutic for the treatment of obesity, both biochemical and cellular based assays will be developed in order to screen for small molecule inhibitors of HMGI-C which may be useful in the treatment of obesity. PROPOSED COMMERCIAL APPLICATIONS: Successful completion of this project would open up new prospects of the discovery of effective, clinically valuable anti-obesity drugs, which would have an enormous commercial potential. It is estimated that the U.S. mark for a prescription anti-obesity drug is approximately $ 1 billion in annual sales. For an over-the-counter drug, potential market is believed to be $10 billion.