Descrizione del progetto
Sulle tracce di una modulazione oppioide della secrezione insulinica
L’obesità e il diabete di tipo 2, che sono interconnessi, sono sempre più diffusi e rappresentano una minaccia significativa per la salute pubblica. Per curarli servono terapie migliori ma la mancanza di comprensione della patologia ostacola lo sviluppo delle terapie. Gli oppioidi hanno un impatto sul metabolismo del glucosio, che può alterare il rischio di sviluppare il diabete. Il progetto OpiO, finanziato dall’UE, studierà il ruolo potenziale del recettore delta-oppioide nel mediare la risposta metabolica agli oppioidi nell’uomo. Inoltre, se il recettore delta-oppioide dovesse svolgere un ruolo diretto nella modulazione della secrezione di insulina da parte del pancreas, il gruppo di ricerca disporrà di un nuovo obiettivo terapeutico per combattere sia l’obesità che il diabete di tipo 2.
Obiettivo
Type 2 diabetes (T2D) and obesity are leading causes of morbidity and mortality, becoming a major burden on public health. Failure to understand their pathophysiology has frustrated efforts to develop improved therapeutic strategies. T2D and obesity are complex polygenic disorders. Genome-wide association studies have identified hundreds of loci associated with metabolic traits, but they have not led to promising new drug targets, so far. In contrast, the identification and characterization of rare mutations causing monogenic metabolic disorders have been instrumental in repositioning or developing drugs. Beyond this proof of concept, the challenge is to use genomic medicine for innovative molecules restoring impaired insulin secretion that characterizes T2D.
OπO has stemmed from the old but forgotten correlation between opioids consumption and metabolic trait abnormalities. Opioids classically act through delta opioid receptor (DOP encoded by OPRD1), kappa and mu opioid receptors. Based on my preliminary data that include large-scale human functional genetics of OPRD1 mutations, my hypothesis is that DOP is a major link between opioids and metabolism in humans. More specifically, I propose that DOP and opioid signaling have a crucial direct role in insulin secretion from pancreatic β cells; making DOP a promising new drug target against T2D.
In this context, I suggest four tasks in OπO: the first two tasks will decipher the role of DOP and opioid signaling in metabolism with a specific focus on islets and β cells, while the two following tasks will decipher the systemic contribution of opioids and opioid receptors to metabolism.
The methodologies that I proposed are truly comprehensive and innovative as they combine preclinical animal studies (with a humanized mouse model), deep phenotyping of islets, pharmacology, multi-omic analyses, genome editing, functional genetics, genetic epidemiology (including Mendelian randomization) and clinical intervention study.
Campo scientifico
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- medical and health sciencesbasic medicinephysiologypathophysiology
- medical and health sciencesclinical medicineendocrinologydiabetes
- natural sciencesbiological sciencesgeneticsmutation
- medical and health scienceshealth sciencesnutritionobesity
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-AG - HORIZON Action Grant Budget-BasedIstituzione ospitante
75654 Paris
Francia