Uncovering Protein Mechanics in Physiology and Disease

Descripción del proyecto

Estudiar las perturbaciones de la mecánica de la titina

Las proteínas, que desempeñan un papel central en los procesos celulares, ahora pueden manipularse. Se sabe que la mecánica de las proteínas contribuye a la función de los sistemas biológicos, la pregunta es cómo y si la alteración de esta mecánica puede desencadenar enfermedades, concretamente afecciones mecánicas como las cardiomiopatías. El proyecto ProtMechanics-Live, financiado por el Consejo Europeo de Investigación, se basará en conocimientos especializados únicos en mecánica e ingeniería de proteínas, biofísica, bioquímica y biología cardiovascular. Su objetivo es permitir la investigación de la mecánica de las proteínas en su contexto fisiológico funcionalmente relevante. Concretamente, el proyecto utilizará herramientas pioneras exclusivas con la titina, la proteína más grande conocida. Estudiará la manera en que las perturbaciones en la mecánica de la titina resultan en la alteración de la fuerza de los cardiomiocitos, su mecanosensibilidad, su mecanoconstrucción, su diferenciación y su proliferación.

Objetivo

Protein mechanics is a key contributor to the form and function of biological systems by mechanisms that are just starting to be unraveled. An ensuing hypothesis is that alteration of protein mechanics can trigger disease, particularly in mechanical conditions such as cardiomyopathies in which primordial underlying molecular mechanisms remain elusive. Although tempting, this possibility has not been tested due to the absence of methods that can modulate the mechanics of proteins in vivo. My proposal aims to overcome technical barriers to scientific progress by establishing manipulation of protein mechanics in living cells and animals as a new research field. In aim 1, we will address current technological limitations through the generation of genetic, protein-engineering-based mechanical loss- and gain-of-function models to interfere acutely and reversibly with protein mechanics in living systems (mLOF and mGOF, respectively). We will apply these first-of-their-kind tools to the giant protein titin, a major contributor to the force-generating and sensing properties of cardiomyocytes with strong links with heart disease, and a workhorse protein that has been instrumental in the past to understand the biophysics of polypeptides under force. In aim 2, we will exploit cellular mLOF and mGOF to define how perturbations of titin mechanics result in altered cardiomyocyte force generation, mechanosensing, mechanotransduction, differentiation and proliferation. Leveraging on our cell studies, in aim 3 we will use murine mLOF and mGOF to shed light into the contribution of titin mechanics to the onset and progression of genetic and acquired cardiomyopathy. ProtMechanics-Live builds on our unique expertise in protein mechanics and engineering, biophysics, biochemistry and cardiovascular biology to enable investigation of mechanical proteins in their functionally relevant, physiological context