Descripción del proyecto
Efectos rejuvenecedores de la alimentación
El estrés desencadena la liberación de hormonas glucocorticoides, asociadas a trastornos cardiometabólicos. Aunque determinadas intervenciones alimentarias como la restricción calórica pueden ayudar a la función metabólica, también aumentan los niveles de glucocorticoides, por lo que no está claro si sus beneficios se deben a esta hormona o a pesar de ella. El equipo del proyecto GRACE, financiado por el Consejo Europeo de Investigación, trabajará sobre la hipótesis de que los beneficios de la restricción calórica se deben al aumento de los niveles de glucocorticoides. El proyecto propone estudiar los efectos moleculares y fisiológicos del aumento de las concentraciones hormonales. Su objetivo es identificar vías y genes que puedan utilizarse para prolongar la vida y mejorar la salud.
Objetivo
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.
Ámbito científico
Palabras clave
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
HORIZON-ERC - HORIZON ERC GrantsInstitución de acogida
80333 Muenchen
Alemania