Descripción del proyecto
Tratar el riesgo de enfermedad cardiovascular en diabéticos
La diabetes guarda relación con enfermedades microvasculares que afectan sobre todo a las arterias coronarias y periféricas, y sin embargo, las terapias modernas contra la diabetes no reducen los episodios cardiovasculares. El proyecto RGD-Diabetes, financiado por el Consejo Europeo de Investigación, subsanará este problema. En concreto, la investigación tratará sobre una proteína circulante, la proteína de unión al factor de crecimiento insulinoide tipo 1, la cual ha mostrado varias características positivas como sensibilización a la insulina, alivio de la intolerancia a la glucosa, reducción de la tensión arterial, aterosclerosis más leve y mayor reparación de lesiones vasculares. En estos efectos media la interacción del dominio RGD de la proteína con receptores de integrina α5β1 superficiales, lo que aumenta la absorción de glucosa estimulada por la insulina en células musculoesqueléticas y la secreción de glucosa estimulada por la insulina en islotes de Langerhans. El proyecto comprobará si la interacción de la integrina RGD pudiera ser aprovechada en tratamientos terapéuticos contra la diabetes.
Objetivo
In Europe, 58 million people are living with type 2 diabetes and 36 million people are at risk of developing the condition. Macrovascular disease is the commonest cause of morbidity and mortality in type 2 diabetes, yet current diabetes therapies have failed to consistently reduce cardiovascular events. In my Starting Grant, I discovered that a circulating protein, IGF binding protein-1, possesses several favourable characteristics– including insulin sensitisation, amelioration of glucose intolerance, blood pressure lowering, reduced atherosclerosis and increased vascular repair. These effects are mediated by interaction of the protein’s RGD-domain with cell-surface α5β1 integrin receptors, which increases insulin-stimulated glucose uptake in skeletal muscle cells and glucose-stimulated insulin secretion in pancreatic islets. Hence the ‘idea’ from my Starting Grant is that RGD-integrin interaction could be exploited therapeutically in diabetes. In this Proof-of-Concept grant, we will take the first step towards commercialisation of the idea by designing and testing small molecule mimics of the RGD domain of IGFBP1 as diabetes therapeutics. Using in silico modelling based on the known structures of IGFBP1 and the α5β1 integrin ectodomain, we will design a small molecule library of commercially available potential agonists. We will carry out virtual high throughput screening of the library for molecules matching the shape and electrostatic potential of the RGD domain of IGFBP1 as predicted to bind to α5β1 integrin. As contingency, we will also identify in silico ‘me-too’ analogues of known integrin ligands. We will test the best quality hits through ADME profiling and validate therapeutic activity in vitro and in vivo. At the end of the project, we anticipate we will have identified small molecule RGD mimics which can subsequently be progressed through the drug-discovery pipeline through translation grant funding or pharmaceutical industry Open Innovation schemes.
Ámbito científico
Programa(s)
Régimen de financiación
ERC-POC - Proof of Concept GrantInstitución de acogida
LS2 9JT Leeds
Reino Unido