Descripción del proyecto
Descodificación de los mecanismos de un nuevo tratamiento para la insuficiencia cardiaca
La fosforilación y la desfosforilación son la adición y la eliminación de grupos de fosfato por parte de quinasas y fosfatasas respectivamente. Las células utilizan constantemente estos procesos para modificar la actividad de las proteínas, unas modificaciones que son fundamentales para diversas funciones celulares, como la señalización cardiaca y la homeostasia del calcio. La desregulación de una fosfatasa proteica específica, PP1, está vinculada con patologías cardiacas. Un grupo de científicos ha desarrollado recientemente unos péptidos, conocidos como péptidos perturbadores de PP1 (PDP, por sus siglas en inglés), que han demostrado tener efectos terapéuticos en el corazón, si bien todavía no se conocen claramente sus mecanismos. Dados los muchos sustratos potenciales de la fosfatasa, resulta difícil identificar estos mecanismos. Gracias a la financiación europea del proyecto PDPcardio, un grupo de desarrolladores de PDP ahora trabaja en métodos nuevos para identificar el alcance de sus acciones, de forma que preparan el terreno para terapias cardiacas que actúen de forma específica y eficaz sobre la fosfatasa.
Objetivo
Protein phosphatase-1 (PP1) is a ubiquitously expressed enzyme known to dephosphorylate a large number of the phosphorylated serines and threonines. The catalytic subunit PP1c is bound to regulatory proteins in holoenzymes. These play specific and fundamental roles in physiological processes and pathologies. One key role lies in the regulation of important cardiac signaling pathways and calcium homoeostasis. Accordingly, deregulation of PP1 has been implicated in cardiac dysfunctions. Powerful tools to study PP1 biology are our own developed PP1-disrupting peptides (PDPs) that selectively release PP1c (bound to PDP: PDP–PP1c) activity in cells. Recently, we showed that PDP treatment counteracts kinase hyperactivity and seals the arrhythmogenic sarcoplasmic reticulum (SR)-calcium-leak in human heart failure tissue. Mechanistic data indicated that PDP–PP1c-mediated dephosphorylation of the ryanodine receptor type 2 (RyR2) is involved in this effect. Nevertheless, given the large amount of potential PP1 substrates, so far the scope of PDP action is unknown, and therefore the mechanisms underlying this beneficial and potentially therapeutic effect of the PDPs in heart failure are unclear and currently hard to investigate. PDPcardio will address these challenges by providing new chemical biology methodologies combined with proteomics approaches using PDPs to guide PP1c to its substrates and to identify PDP-mediated interactions of PP1. These strategies will enable identifying the scope of PDP action in general, and in particular they will be applied here in cardiomyocytes to study the effects of PDP–PP1c. The results will provide the basis to fine-tune targeting PP1 for the treatment of heart insufficiency. Furthermore, the principles and methods developed here will be applicable more generally for defining the interaction scope of target-bound ligands (drugs) as well as for using PP1 as tool in synthetic biology.
Ámbito científico
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- natural sciencesbiological sciencessynthetic biology
- natural scienceschemical sciencesinorganic chemistryalkaline earth metals
- medical and health sciencesbasic medicinepathology
- medical and health sciencesclinical medicinecardiology
Palabras clave
Programa(s)
Régimen de financiación
ERC-COG - Consolidator GrantInstitución de acogida
79098 Freiburg
Alemania