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Gut-Brain Communication in Metabolic Control

Descrizione del progetto

Comunicazione intestino-cervello e obesità

La comunicazione neurale tra intestino e cervello aiuta a monitorare gli organi dell’apparato gastrointestinale e contribuisce alla regolazione dell’omeostasi di energia e glucosio. La sua alterazione evolve nell’obesità ed è correlata a sovralimentazione e insulino-resistenza. Questo progetto finanziato dall’UE, impiegherà una combinazione di moderni strumenti di neuroscienza molecolare e approcci di genetica murina, per stabilire l’identità dei neuroni che innervano l’intestino, definire il loro ruolo nel comportamento alimentare e nel metabolismo del glucosio, nonché per mappare il circuito neuronale verso i siti cerebrali a valle. Il risultato positivo del progetto aiuterà a superare le difficoltà correlate all’intervento su neuroni distinti, con una modalità specifica per l’organo e per tipo di cellula, una prima fase importante per sviluppare nuove terapie per il trattamento dell’obesità.

Obiettivo

Communication between the gut and the brain is essential for metabolic function. Sensory afferent neurons are key gut-brain connectors that monitor gastrointestinal (GI) tract organs, including the stomach, the duodenum, the liver, and the portal vein area, and thereby critically contribute to systemic energy and glucose homeostasis regulation. Disruption of this neural gut-brain communication develops in obesity and correlates with overeating, body weight gain, and insulin resistance. However, the relevant sensory neuronal populations innervating the GI tract organs along with the pertaining underlying metabolic neurocircuitry still remain to be elucidated. To date, advances in this field have been impeded by the challenges associated with targeting distinct sensory neurons of vagal and spinal origin in a cell-type and organ-specific manner, thereby making the accurate determination of their metabolic function highly difficult. Thus, the proposed comprehensive research program will employ a combinatorial set of modern molecular systems neuroscience tools and novel mouse genetic approaches to (1) elucidate the role of specific sensory neurons in feeding behavior and glucose metabolism, (2) determine the functional metabolic neurocircuitry of GI tract-innervating vagal and spinal afferents in an organ-specific manner, (3) study the effects of obesity on their transcriptomes, and (4) map their functional connectivity as well as synaptic adaptions to downstream brain sites. Collectively, the overarching goals of these four autonomous but complementary projects are to gain greater insights into the integral components of sensory neurons as gut-brain connectors in controlling metabolism as a first step to developing new therapies to treat obesity.