Descrizione del progetto
Effetti ringiovanenti della dieta
Lo stress innesca il rilascio di ormoni glucocorticoidi che sono associati a disturbi cardiometabolici. Sebbene alcuni interventi dietetici, come la restrizione calorica, possano aiutare la funzionalità metabolica, essi aumentano anche i livelli di glucocorticoidi, quindi non è chiaro se i loro benefici siano dovuti o meno a questo ormone. Finanziato dal Consiglio europeo della ricerca, il progetto GRACE lavorerà sull’ipotesi che i benefici della restrizione calorica siano dovuti all’aumento dei livelli di glucocorticoidi. Il progetto si propone di studiare gli effetti molecolari e fisiologici dell’aumento dei livelli ormonali. Auspica di identificare percorsi e geni che possano essere presi di mira per promuovere una vita più lunga e più sana.
Obiettivo
The pandemic is stressful for many. In response to stress, glucocorticoids are released. They play essential roles as endogenous hormones and clinically as drugs. High levels are associated with cardiometabolic disorders and with aging. In contrast, diets like caloric restriction ameliorate metabolic dysfunction and prolong lifespan. These diets, however, also increase glucocorticoids. Now the open question is: What are the molecular and physiological effects of increased hormone levels, and are these diets beneficial because or in spite of elevated glucocorticoids?
We recently found that nutrition reprograms glucocorticoid responses independently of the hormone level and that diurnal glucocorticoid action controls rhythmic gene expression to regulate circulating glucose and triglycerides during day and night. I hypothesize that the benefits of caloric restriction are due to higher glucocorticoid amplitudes, and that their study will uncover transcriptional features prolonging healthspan.
I propose to functionally distinguish between diet-induced positive and stress-induced negative glucocorticoid responses. GRACE will identify diet-specific, ‘rejuvenating’ transcriptional complexes and target genes, versus detrimental pathways triggered by excess glucocorticoids such as stress. Glucocorticoid receptor targets unique to caloric restriction will be determined via ChIP- and RNA-seq in Aim 1. The functional impact of diurnal glucocorticoid release will be dissected with a constitutively active receptor allele in Aim 2. I propose to map active transcriptional regulomes in caloric restriction, in youth and old age, by ChIP-MS in Aim 3. I postulate that enhanced glucocorticoid activity at the right time of day may boost circadian rhythms and promote longevity.
Ultimately, applying omics to study the molecular mechanisms of stress hormones will identify pathways and genes amenable to pharmacological or nutritional intervention for longer, healthier lives.
Campo scientifico
Parole chiave
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-ERC - HORIZON ERC GrantsIstituzione ospitante
80333 Muenchen
Germania