Descrizione del progetto
Una nuova alba nello sviluppo di farmaci contro l’obesità
L’obesità, che sta determinando una crisi crescente della sanità pubblica, è accompagnata da un’allarmante impennata di disturbi cronici, quali il diabete, le malattie cardiovascolari e il cancro. Il complesso controllo dell’equilibrio energetico, che viene gestito dal nucleo arcuato dell’ipotalamo, svolge un ruolo fondamentale in tal ambito; tuttavia, nonostante siamo a conoscenza di questo meccanismo di regolazione centrale, non disponiamo tuttora di trattamenti efficaci. Con il sostegno del programma di azioni Marie Skłodowska-Curie, il progetto FEEDING mira a comprendere meglio questa complessità avventurandosi nel territorio inesplorato dei recettori orfani accoppiati a proteine G e approfondendo inoltre la loro interazione con i recettori della leptina. Attraverso l’ingegnoso impiego di modelli knockout, agenti farmacologici e valutazioni metaboliche, gli scienziati si propongono di decifrare il codice della resistenza alla leptina, intraprendendo un’iniziativa che dispone del potenziale per ridefinire la battaglia contro l’obesità.
Obiettivo
"Obesity is a major burden to public health as it increases the risk of several chronic diseases, like diabetes, cardiovascular diseases, musculoskeletal disorders or some cancers. Energy homeostasis is centrally regulated by the hypothalamus where the arcuate nucleus (ARC) orchestrates feeding behaviors and energy balance. Two neuronal populations of the ARC are considered as the first-order neurons mediating the effects of various signals such as leptin and insulin, the orexigenic neuropeptide (NP)Y/Agouti-related peptide (AgRP) neurons and the anorexigenic pro-opiomelanocortin (POMC)/Amphetamine-regulated transcript (CART) neurons. Leptin is an adipocyte-secreted peptidic hormone that inhibits food intake and regulates body weight. Nearly in all forms of obesity, circulating levels of leptin increase but fail to suppress food intake and body weight. This condition has been identified as ""leptin resistance"".
G protein-coupled receptors (GPCRs) are the largest family of membrane proteins and a notoriously successful source of drug targets. However, many GPCRs are understudied or even orphans meaning they have no known ligands. Despite our knowledge of the principal circuits regulating feeding, satiety, hunger and energy expenditure, we have been unable to deliver effective drugs targeting these systems. The failure in targeting the melanocortin pathways comes out partly from an incomplete understanding of leptin action, especially leptin resistance, at the central level. Here, we propose to investigate the interplay between the signaling of orphan GPCR and leptin receptor in leptin sensitive cells of the arcuate nucleus. To do so, we will use conditional knockout animals and pharmacological modulators. We will measure various metabolic parameters including weight and food intake with the Comprehensive Laboratory Animal Monitoring System (CLAMS). We will also establish hypothalamic cell cultures in which we will address the impact of G protein signaling on leptin."
Campo scientifico
- medical and health scienceshealth sciencespublic health
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesclinical medicinecardiologycardiovascular diseases
- medical and health sciencesbasic medicinephysiologyhomeostasis
- medical and health scienceshealth sciencesnutritionobesity
Parole chiave
Programma(i)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Meccanismo di finanziamento
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinatore
4000 Liege
Belgio