INSULIN RESISTANCE · Control of insulin sensitivity through transcriptional co-factors: implications for type II diabetes therapy
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2005-08-01 → 2009-07-31
- EU contribution
- €1,756,245
- Participants
- 1
- Scheme
- EXT
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Results in brief
Final Activity Report Summary - INSULIN RESISTANCE (Control of insulin sensitivity through transcriptional co-factors: implications for type II diabetes therapy)
Research has been focused on the transcriptional control of metabolism and its contribution to the development of metabolic diseases such as type II diabetes, atherosclerosis and cancer cachexia. The development of resistance against the pancreatic hormone insulin is the common hallmark of these disorders and represents an increasingly important threat to public health worldwide. By analysing signal-dependent transcription factor action, we have aimed to ultimately decipher the molecular basis for insulin resistance and the subsequent defects in energy homeostasis. In this respect, our work has been able to identify novel transcriptional co-factor complexes as integrative sites for dietary, inflammatory, and hormonal pathways, thereby impacting both pro-inflammatory and metabolic programs in critical target tissues and determining systemic energy homeostasis. Furthermore, the Marie Curie Excellence team has unravelled an as-yet unappreciated involvement of inflammatory mediators in the control of systemic energy balance through the modulation of adipocyte progenitor cell fate decisions. Together, our studies have been able to establish novel transcriptional signalling pathways and mechanisms in the integration of metabolism and inflammation, thereby substantially expanding the understanding of this increasingly important aspect of insulin resistance and its associated disorders. Individual pathways components will now help to improve therapeutic options in the treatment of chronic inflammatory, insulin resistant conditions such as cancer cachexia and the Metabolic Syndrome.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- DEUTSCHES KREBSFORSCHUNGSZENTRUM · HEIDELBERGCoordinatorGermany
Links
Data: CORDIS, © European Union