The overarching goal of our laboratory's research is to better understand the pathogenesis of type 2 diabetes and develop therapeutic manipulations to improve these outcomes. Our NIH K01 funded research into mechanisms driving insulin resistance in adipose tissue utilized unbiased quantitative proteomics to identify novel pathways. One of the top hits from this approach identified activation of ERK Kinase leading to transcriptional alterations in adipose tissue via dysregulation of PPAR?. Although much is known about the biology of ERK in the context of oncology and signal transduction, much less is known about the role in the pathogenesis of obesity, insulin resistance and diabetes. Indeed, MEK inhibitors capable of completely blocking ERK activation have recently been approved by the FDA. These compounds effective in both patients and mouse models at delaying the growth of certain cancers. Our preliminary data demonstrate that treating obese, insulin resistant mice with MEK inhibitors improves whole body glucose homeostasis in part through improvements in transcriptional activation of PPAR ? target genes. In this proposal we aim to identify the mechanisms responsible for these beneficial effects.
In specific aim 1 we will examine the PPAR?-dependent and -independent effects of MEK/ERK inhibitors.
In specific aim 2 we will examine the transcriptional and proteomic consequences of MEK/ERK to identify targets of ERK action in vivo. These data would build upon the findings from the K01 award, be completed in a defined award period, and potentially contribute toward novel treatments for type 2 diabetes that could be rapidly translated to clinical investigation.
While great progress has been made in decreasing the rate of death from cardiovascular diseases, stroke and even cancer, diabetes related morbidity and mortality remain a steady threat to the US population. This work will help to test whether an existing cancer drug can be repurposed for treating diabetes. Should we find this drug safe and effective, this could rapidly be a new treatment available for patients.
| Palmer, Colin J; Bruckner, Raphael J; Paulo, Joao A et al. (2017) Cdkal1, a type 2 diabetes susceptibility gene, regulates mitochondrial function in adipose tissue. Mol Metab 6:1212-1225 |
