Descripción del proyecto
Revelar los misterios del colesterol y la ingesta de azúcar
Las enfermedades cardiovasculares, la diabetes y el cáncer siguen causando estragos en la sociedad, y el colesterol y la ingesta de azúcar desempeñan un papel fundamental en su desarrollo. A pesar de los muchos años de investigación, los mecanismos moleculares que favorecen estos procesos siguen rodeados de misterio. El equipo del proyecto CSUMECH, financiado por el Consejo Europeo de Investigación, se ha propuesto revelar estos misterios utilizando métodos de vanguardia como la cristalografía macromolecular y la microscopia electrónica. Gracias a CSUMECH se podría descubrir y aportar conocimientos revolucionarios de la bioquímica humana. Al arrojar luz sobre los principios fundamentales de los sistemas de captación endocítica y difusión facilitada, este proyecto puede abrir camino a otros descubrimientos interesantes en el ámbito de la bioquímica humana y contribuir a mejorar la salud pública en todo el mundo.
Objetivo
Cardiovascular disease, diabetes and cancer have a dramatic impact on modern society, and in great part are related to uptake of cholesterol and sugar. We still know surprisingly little about the molecular details of the processes that goes on in this essential part of human basic metabolism. This application addresses cholesterol and sugar transport and aim to elucidate the molecular mechanism of cholesterol and sugar uptake in humans. It moves the frontiers of the field by shifting the focus to in vitro work allowing hitherto untried structural and biochemical experiments to be performed.
Cholesterol uptake from the intestine is mediated by the membrane protein NPC1L1. Despite extensive research, the molecular mechanism of NPC1L1-dependent cholesterol uptake still remains largely unknown.
Facilitated sugar transport in humans is made possible by sugar transporters called GLUTs and SWEETs, and every cell possesses these sugar transport systems. For all these uptake systems structural information is sorely lacking to address important mechanistic questions to help elucidate their molecular mechanism.
I will address this using a complementary set of methods founded in macromolecular crystallography and electron microscopy to determine the 3-dimensional structures of key players in these uptake systems. My unpublished preliminary results have established the feasibility of this approach. This will be followed up by biochemical characterization of the molecular mechanism in vitro and in silico.
This high risk/high reward membrane protein proposal could lead to a breakthrough in how we approach human biochemical pathways that are linked to trans-membrane transport. An improved understanding of cholesterol and sugar homeostasis has tremendous potential for improving general public health, and furthermore this proposal will help to uncover general principles of endocytotic uptake and facilitated diffusion systems at the molecular level.
Ámbito científico
- natural sciencesearth and related environmental sciencesgeologymineralogycrystallography
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesphysical sciencesopticsmicroscopyelectron microscopy
- medical and health sciencesbasic medicinephysiologyhomeostasis
- natural sciencesbiological sciencesmolecular biologystructural biology
Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
8000 Aarhus C
Dinamarca