Grants and Contracts Details
Obesity is prevalent worldwide and is associated with insulin resistance and the development of type 2 diabetes. Obesity is now recognized as a state of chronic low-grade systemic inflammation which promotes the development of insulin resistance and other metabolic complications. Adipose tissue is a key organ for this chronic inflammatory response. Increased accumulation of adipose tissue macrophages (ATMs) has been demonstrated in obese rodents and humans by numerous studies. It is now well established that ATMs are the primary source of inflammatory cytokine production in adipose tissue and play a key role in obesity-induced chronic low-grade inflammation and insulin resistance. Although there have been some advances in the study of ATMs in obese conditions, the mechanisms underlying inflammatory cell recruitment and activation remain to be determined. Thrombospondin 1 (TSP1) has been identified to be an adipokine and its expression levels correlate positively with human obesity, adipose tissue inflammation and insulin resistance. By using TSP1 deficient mice, preliminary studies revealed a novel role for TSP1 in regulating macrophage function (motility and activation) and its contribution to obesity-induced inflammation and insulin resistance in a high fat diet induced obesity mouse model. Moreover, TSP1 promoting macrophage migration and activation is through N-terminal domain and type 1 repeats to interact with receptors LRP1 and CD36, respectively. Based on these data, we hypothesize that blockade of the effect of stimulatory domain of TSP1 on macrophage function prevents/ameliorates obesity associated inflammation and insulin resistance. To test this hypothesis, in Aim 1, the significance of adipocyte or macrophage derived TSP1 in the development of obesity-associated inflammation and insulin resistance will be determined suing our newly generated TSP1 conditional knock out mice. In Aim 2: new decoy peptides to block TSP1 stimulatory effects on macrophage migration and activation will be designed and tested in vitro as well as in vivo. In Aim 3, the effect of specific blocking of the TSP1/CD36 interaction by a known peptide derived from CD36 on obesity-induced inflammation and insulin resistance will be determined. These studies will test the novel therapeutic potential for the effects of blocking TSP1/CD36 interaction by a known CD 36 peptide on obesity associated inflammation and IR in a DIO mouse model (Aim 3). In addition, new decoy peptides to specifically block the effect of stimulatory domains of TSP1 on macrophage function will be designed by structure-based computational design approach, which has been proven to be fast, efficient and economical as compared to the traditional random screening approach to drug discovery. Together, these proposed studies may lead to novel therapeutic treatment for obesity induced IR and metabolic complications, and therefore, have significant clinical relevance.
|Effective start/end date
|8/20/14 → 5/31/21
- National Institute Diabetes & Digestive & Kidney: $1,204,816.00
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