VALIDATION OF HMGI-C AS A DRUG TARGET IN OBESITY

HMGI-C 作为肥胖症药物靶点的验证

• 批准号: 6143070
• 负责人: ROLAND A CHOUINARD
• 金额: $ 37.67万
• 依托单位: HMGENE, INC.
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-15 至 2002-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6143070
• 关键词: adipocytes; adipose tissue; body composition; cell differentiation; differential display technique; drug design /synthesis /production; drug discovery /isolation; gene expression; genetic regulatory element; genetically modified animals; laboratory mouse; leptin; lipid biosynthesis; microarray technology; obesity; transcription factor

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.

HMGene 治疗肥胖症的独特新颖方法是开发直接作用于脂肪组织的药物。 II 期的目标是进一步验证 HMGI-C（一种调节脂肪生成中基因表达的结构转录因子）作为肥胖症的药物靶点。在第一阶段，研究表明 HMGI-C 失活可以逆转瘦素缺乏引起的肥胖。第二阶段将扩展这些研究，以表明饮食引起的肥胖也是如此，这是一种更符合生理学的模型，更接近于人类疾病。由于 HMGI-C 是一种转录调节因子，位于基因组级联的顶端，因此 DNA 微阵列和 RNA 差异显示技术将用于识别 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疗法，因此将开发基于生化和细胞的测定法，以筛选可用于治疗肥胖症的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、有临床价值的抗肥胖药物开辟新的前景，这将具有巨大的商业潜力。据估计，美国抗肥胖处方药的年销售额约为 10 亿美元。对于一种非处方药，潜在市场据信为 100 亿美元。