Hypertension pharmacotherapy, albeit fairly effective, is far from ideal and adequate blood pressure control is only achieved in one third of patients. As such, hypertension is still the global leading cause of cardiovascular disease and mortality. In this regard, we have recently discovered that higher intake of the caloric restriction mimetic spermidine – a potent inducer of the cellular quality control mechanism, autophagy – correlates with lower blood pressure in humans. Administering spermidine to animals also delays the development of hypertension and vascular aging, suggesting it might be useful for disease prevention. However, whether spermidine can be used for therapy, as urgently needed in patients, is still unknown. Thus, the main objective of this proposal is to elucidate the therapeutic benefit of spermidine in established experimental hypertension. Applying a multitude of cutting-edge techniques, including knockout of autophagy genes and metabolic flux, we will provide key mechanistic insights on whether spermidine counteracts hypertension via activating autophagy, upregulating the arginine-nitric oxide axis, or both. With the ultimate goal of translating our findings from animals to humans, we will validate the clinical relevance of these mechanisms in patients' samples. Hence, this proposal will not only reveal a potential novel treatment for patients with hypertension, but will also study a previously understudied cross-talk between blood pressure control and autophagy. If true, we anticipate the project results to pave the way for a novel concept for hypertension therapy. Considering that the work will be done at a leading multi-disciplinary research group, where the researcher will bring expertise in cardiology and receive advanced training in cell biology and molecular metabolism, the fellowship will substantially advance his academic career to eventually reach his goal of leading his own research team.
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