Descripción del proyecto
Comprensión del control neuroendocrino del apetito
Hoy día no existen terapias eficaces contra la obesidad, que constituye uno de los principales retos médicos de las sociedades modernas. Para diseñar tratamientos novedosos, es necesario comprender la manera en la que el sistema nervioso controla el apetito. En el proyecto Ob_GLP1, financiado con fondos europeos, se investigará el sistema del péptido semejante al glucagón de tipo 1(GLP-1) en el encéfalo, que desempeña un papel en la secreción de insulina. Los agonistas que se unen a los receptores de GLP-1 en el encéfalo promueven la liberación de insulina y pueden usarse para tratar la diabetes de tipo 2. Los investigadores del proyecto estudiarán la distribución y función de los receptores de GLP-1 en el encéfalo para proporcionar conocimientos fundamentales sobre el control encefálico de la obesidad y ayudar a diseñar nuevos tratamientos contra esta enfermedad.
Objetivo
Obesity is a major health challenge in the EU and globally, and yet the best drug therapies achieve only modest reductions in weight loss and require life-long treatment. To prevent and treat obesity it is crucial we understand the neural pathways controlling appetite and how they can be ‘hijacked’ therapeutically. The brain glucagon-like peptide-1 (GLP1) system is a promising target. GLP1 receptor agonists (GLP1RAs) decrease food intake and bodyweight in obese patients, effects which are mediated by two brain regions: the arcuate nucleus of the hypothalamus (Arc) and the nucleus of the solitary tract (NTS). This project, Ob_GLP1, combines the neuroscience background of Dr Holt with the next-generation technology and imaging expertise of Dr Hodson to test the hypothesis that obesity disrupts the function of GLP1RA-responsive Arc and NTS circuits and that obesity can be rescued by selectively targeting intracellular signalling in GLP1RA-activated neurons. This hypothesis will be tested through the completion of four independent, yet complementary work packages. Work package 1-3 will determine the effect of obesity on 1) GLP1RA access to the Arc and NTS measured using fluorescently labelled GLP1R antagonist and whole-brain light-sheet microscopy; 2) the molecular distribution and oligomerisation state of GLP1Rs in the Arc and NTS; and 3) the innervation pattern and synaptic density of Arc and NTS GLP1R neurons. Work package 4 will assess the potential of a novel GLP1-conjugated antisense nucleotide as an effective anti-obesity treatment. Ob_GLP1 will advance our knowledge of the brain’s control over obesity, while allowing Dr Holt to reintegrate into the European research environment and will facilitate substantial two-way transfer of knowledge between the host lab and Dr Holt, ultimately benefitting both parties, as well as society as a whole.
Ámbito científico
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
B15 2TT Birmingham
Reino Unido