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Control of insulin sensitivity through transcriptional co-factors: implications for type II diabetes therapy

Objective

According to WHO estimates, 300 million people will be diagnosed with type II diabetes in 2025 worldwide. The development of resistance against the pancreatic hormone insulin is the hallmark of diabetic pathogenesis. Importantly, insulin resistance is not only associated with the diabetic state but is intimately linked to cancer cachexia, obesity, and the adverse effects of aging, all of which become increasingly important threats to public health in European countries.

Insulin resistance in skeletal muscle is the first lesion in individuals with type II diabetes susceptibility. The molecular mechanisms leading to its manifestation are still unknown, thereby, preventing the development of effective treatment strategies. To this end, the hormone-dependent activity of transcriptional co-factors, such as nuclear receptor co-factor RIP140, has been established by our previous studies as a critical switch in the control of insulin-sensitive metabolic pathways in other tissues. Consequently, by using viral gene therapy and functional genomics approaches, the major objective of this proposal is to uncover the molecular function of RIP140 in skeletal muscle and to determine its role in the development of insulin resistance in metabolic diseases.

To this end, we aim to identify RIP140 target gene networks in muscle and, by combining chemistry, pharmacology and bioinformatics in an interdisciplinary approach, to establish nuclear RIP140-interacting proteins as novel targets for therapeutic synthetic compounds. This study will substantially elucidate molecular mechanisms of peripheral insulin resistance and define the transcriptional co-factor RIP140 as a prototypic molecular target for innovative therapy of metabolic diseases, such as type II diabetes and cancer cachexia. In this regard, the current proposal displays significant overlap with the priority of the FP6 to combat chronic diseases and will substantially strengthen European research activities in this area.

Call for proposal

FP6-2002-MOBILITY-8
See other projects for this call

Funding Scheme

EXT - Marie Curie actions-Grants for Excellent Teams

Coordinator

DEUTSCHES KREBSFORSCHUNGSZENTRUM
Address
Im Neuenheimer Feld 280
Heidelberg
Germany