Descripción del proyecto
Orgánulos sintéticos para el tratamiento de la esteatosis hepática no alcohólica
La esteatosis hepática no alcohólica (EHNA) se caracteriza a nivel celular por varias deficiencias enzimáticas, incluida la reducción de la biosíntesis de S-adenosilmetionina (SAMe). Por lo tanto, se ha propuesto el mantenimiento de la actividad de la enzima SAMe sintetasa como un posible tratamiento para hepatopatías como la EHNA. El objetivo del proyecto MetD-AO, financiado con fondos europeos, es desarrollar orgánulos sintéticos para sustituir la ausencia o pérdida de la actividad biocatalítica de la SAMe sintetasa en los hepatocitos. La composición de estos orgánulos sintéticos facilita el escape lisosomal y garantiza una actividad enzimática eficaz, lo que permite solventar las limitaciones previas. Se espera que los resultados allanen el camino para el desarrollo de tratamientos innovadores para las hepatopatías.
Objetivo
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world, encompassing a spectrum of liver damage. Multiple issues are involved on the cellular level in failing liver often including enzyme deficiencies such as reduced biosynthesis of S-adenosylmethionine (SAMe). Preserving SAMe homeostasis has only recently started to be considered as a potential therapeutic target in liver-related medical conditions. However, employing the required enzyme, SAMe synthetase (SAMe-synth), as a pharmaceutical, is challenging due to the general issues involved in intact (functional) protein delivery.
The aim of the MetD-AO project is to assemble organic SAMe-synth activity mimicking polymer nanoparticles as artificial organelles (AO) and their in vitro characterization of intracellular function in hepatocytes. AOs are typically nano-sized single compartment reactors, aimed to perform a specific encapsulated biocatalytic reaction within a cell to substitute for missing or lost function. The AO will be based on amphiphilic copolymers consisting of a methyl-donating unit, cholesterol methacrylate and poly(5-carboxypentyl acrylate) as membranolytic hydrophilic tail. The latter two will aim at facilitating self-assembly and lysosomal escape, respectively. To allow structurally intact AO to escape the lysosome is unique since typically, the carrier is destroyed and only the therapeutic cargo is release into the cytosol. The proposed AOs with methyl-donating ability are highly advanced because the few prior reported AOs with intracellular activity all considered reactive oxygen related aspects at best. The successful outcome of MetD-AO has the potential to open up entirely new therapeutic opportunities in NAFLD.
The complementary expertise of my host Dr. Stadler and me, a trained polymer chemist, will ensure a successful conduction of MetD-AO while it will enhance my future career prospects gaining experience in colloidal science and cell biology.
Ámbito científico
Programa(s)
Régimen de financiación
MSCA-IF-EF-ST - Standard EFCoordinador
8000 Aarhus C
Dinamarca