Descripción del proyecto
Sobre la pista de la modulación de la secreción de insulina con opioides
La obesidad y la diabetes de tipo 2 están relacionadas entre sí, son cada vez más frecuentes y plantean una amenaza importante para la salud pública. Se necesitan tratamientos mejorados, pero la falta de conocimiento de la patología de estas enfermedades ha obstaculizado su desarrollo. Los opioides afectan al metabolismo de la glucosa, lo cual puede alterar el riesgo de desarrollar diabetes. El proyecto OpiO, financiado con fondos europeos, investigará un posible papel del receptor de opioides δ en la mediación de la respuesta metabólica a los opioides en humanos. Además, si resulta que el receptor de opioides δ desempeña un papel en la modulación de la producción de insulina por parte del páncreas, el equipo tendrá una nueva diana terapéutica para combatir tanto la obesidad como la diabetes de tipo 2.
Objetivo
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.
Ámbito científico
- 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
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
HORIZON-AG - HORIZON Action Grant Budget-BasedInstitución de acogida
75654 Paris
Francia