The aim of this proposal is to understand a novel regulatory signaling network controlling insulin secretion, fat accumulation and energy balance centered around selected components of the TGF-² signaling system, including Activins A and B, GDF-3 and their receptors ALK7 and ALK4. Recent results from my laboratory indicate that these molecules are part of paracrine signaling networks that control important functions in pancreatic islets and adipose tissue through feedback inhibition and feed-forward regulation. These discoveries have open up a new research area with important implications for the understanding of metabolic networks and the treatment of human metabolic syndromes, such as diabetes and obesity.
To drive progress in this new research area beyond the state-of-the-art it is proposed to: i) Elucidate the molecular mechanisms by which Activins regulate Ca2+ influx and insulin secretion in pancreatic ²-cells; ii) Elucidate the molecular mechanisms underlying the effects of GDF-3 on adipocyte metabolism, turnover and fat accumulation; iii) Investigate the interplay between insulin levels and fat deposition in the development of insulin resistance using mutant mice lacking Activin B and GDF-3; iv) Investigate tissue-specific contributions of ALK7 and ALK4 signaling to metabolic control by generating and characterizing conditional mutant mice; v) Investigate the effects of specific and reversible inactivation of ALK7 and ALK4 on metabolic regulation using a novel chemical-genetic approach based on analog-sensitive alleles.
This is research of a high-gain/high-risk nature. It is posed to open unique opportunities for further exploration of complex metabolic networks. The development of drugs capable of enhancing insulin secretion, limiting fat accumulation and ameliorating diet-induced obesity by targeting components of the ALK7 signaling network will find a strong rationale in the results of the proposed work.
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