SBIR-STTR Award

It is proposed in this application to test whether the DNA binding protein HMGI-C is involved in the development of obesity in the ob/ob mouse. This will be accomplished by breeding ob/ob mice in which one or both HMGI-C alleles have been disrupted, and assessing the impact of these changes on the development of the obese phenotype and its associated abnormalities. The expected result of decreased obesity will provide support for targeting the HMGI-C gene/protein for anti-obesity drug development. Targeted disruption of the HMGI-C gene has been shown by Dr. Chada to result in the pigmy (pg/pg) mouse, which was initially described as a spontaneous mutant with a 20-fold decrease in body fat. This, and the subsequent observations by Dr. Chada's group that mutations of HMGI-C and HMGI-(Y) are found in human lipomas provide the rationale for the proposed studies. Preliminary data is presented that expression of the HMGI-C and HMGI-(Y) genes are elevated in both ob/ob and db/db mice, and that HMGI-C+/- ob/ob mice (N = 2) have delayed weight gain compared to HMGI-C +/+ ob/ob controls. The ob/ob phenotype is considered to be a good model of human obesity that is due to hyperphagia, so that effects of the absence of HMGI-C in mice may have relevance to human obesity.

Thesaurus Terms:
DNA binding protein, gene targeting, nonhistone nucleoprotein, obesity adipose tissue, body composition, drug design /synthesis /production, drug screening /evaluation, leptin, lipid biosynthesis laboratory mouse, transgenic animal

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.

Thesaurus Terms:
adipocyte, cell differentiation, gene expression, obesity, transcription factor adipose tissue, body composition, drug design /synthesis /production, drug discovery /isolation, genetic regulatory element, leptin, lipid biosynthesis differential display technique, laboratory mouse, microarray technology, transgenic animal