Descripción del proyecto
Comprender el papel del entorno mecánico en la remodelación vascular
El fenotipo celular y el destino celular en el aparato circulatorio dependen de las propiedades mecánicas del entorno. Las condiciones mecánicas fisiológicas normales definen y estabilizan el fenotipo celular, mientras que la tensión mecánica aberrante desencadena cambios fenotípicos que conducen a la inflamación y la remodelación vascular. La hipótesis actual es que la transmisión de tensiones mecánicas al núcleo activa vías de señalización, lo que a su vez regula la expresión génica. Sin embargo, a diferencia de la mayoría de las células vasculares, las células madre residentes (CMR) permanecen indiferenciadas, a pesar de la presión constante de los estiramientos cíclicos. El proyecto MechanoFate, financiado por el Consejo Europeo de Investigación, tiene por objeto determinar las vías de mecanotransducción nuclear que regulan las respuestas fenotípicas a las tensiones mecánicas en las tensiones vasculares y los mecanismos moleculares que protegen a las CMR de la diferenciación inducida por el estiramiento.
Objetivo
In the vascular system, cell phenotype and fate are driven by the mechanical environment. Whereas physiological mechanical stress defines and stabilizes normal cell phenotype, aberrant mechanical signals trigger phenotypic alteration, leading to inflammation and vascular remodelling. Despite recent advances, how mechanical cues impact gene expression to specify cell phenotype remains poorly understood.
Our hypothesis is that mechanical stresses are transmitted to the nucleus where they activate signaling pathways, which in turn regulate gene expression, but what are these mechanotransduction mechanisms occurring within the nucleus? Besides, while most vascular cells respond to mechanical force, Resident Stem Cells (RSCs) are virtually insensitive and remain undifferentiated despite constant cyclic stretch. What are the molecular mechanisms which protect RSCs from stretch-induced differentiation?
To answer these questions, we designed an interdisciplinary proposal which gathers biophysical, biochemical and genetic assays, with the following objectives: I) To determine how nuclear mechanotransduction pathways regulate vascular cell phenotype in response to mechanical cues. By combining proteomic and biophysical assays, we will identify nuclear proteins that are post-translationally modified in response to mechanical stress, then we will determine their contribution to gene expression regulation and vascular cell differentiation. II) To identify the molecular mechanisms which protect RSCs from stretch-induced differentiation. We will identify differentially expressed force-bearing structural elements in RSCs compared to more differentiated vascular cells and we will evaluate their impact on gene expression, stress transmission, RSC differentiation and blood vessel formation.The proposed project will yield new insights in different areas of life science from cell biology to potential identification of new therapeutic targets in cardiovascular and regenerative medicine.
Ámbito científico
Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
75654 Paris
Francia