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职业迁徙
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The interplay of cells and tissues with mechanical forces from their environment emerges as a novel key aspect of both organismal homeostasis and disease. The pathophysiology of atherosclerosis is a paradigm example: while most known risk factors are systemic, local disturbed blood flow patterns determine lesion development and progression at specific sites, by sensitizing the endothelium to inflammatory and metabolic factors and eliciting a positive feedback through local arterial wall remodelling and further inflammation. Understanding the principles of integration of mechanical cues with cell function and tissue architecture is required for effective intervention and disruption of these self-sustained mechanisms driving disease progression. Our multidisciplinary research program combines state-of-the-art cell biology, omics and biophysics with advanced mouse models of disease to achieve a global picture of these mechanisms across scales, from molecular architecture to organism.
A major focus of our research is devoted to the structural, molecular and cell biology of caveolae—plasma membrane nanoscale invaginations abundant in mechanically challenged tissues (endothelium, muscle, adipose tissue)—and their main components, caveolins and cavins (del Pozo et al, Curr Op Cell Biol 2020; Echarri and Del Pozo J Cell Sci 2015; del Pozo and Parton, Nat Rev Mol Cell Biol 2013). Apart from allocating signaling modules and organizing membrane trafficking and structure, caveolae undergo reversible flattening upon PM tension increase, in a manner coordinated with actin cytoskeleton dynamics (Echarri et al, Nat Commun 2019; Minguet et al, Nat Immunol 2017; Muriel et al, J Cell Sci 2011; Echarri et al. J Cell Sci 2015 & 2012). We have developed different quantitative approaches to explore the molecular mechanisms governing the architecture and dynamic interactome of caveolae, with a particular interest on their changes during cell mechanoadaptation and their physical and functional contact with other structures in different cell types, such as endothelia, cardiomyocytes and adipocytes. The role of other molecular mechanisms driving cell membrane organization and mechanoadaption, such as Rac1 downstream signaling-driven actin-polymerization, is also studied (Navarro-Lérida et al., Dev Cell 2015 and EMBO J 2012).
A second research interest lies on charting the transduction signaling networks downstream cell mechanosensation, and understanding how they reprogram and coordinate different cell functions (secretion, contractility and motility, metabolism, inflammation) at systems level. We are studying novel molecular mechanisms regulating the YAP mechanotransduction system, which feeds from Cav1-dependent mechanosensing and actin cytoskeletal dynamics (Strippoli et al. Cell Death Diff 2020, Moreno-Vicente et al. Cell Rep 2018). We are also characterizing the role of different membrane trafficking regulators, including Cav1, on the differential responses of endothelial cells to atheroprotective fluid shear versus atherogenic disturbed patterns. Finally, we research the relevance of caveolae-dependent mechanotransduction in adipocytes for metabolic homeostasis: an insufficient physical capacity to expand and accommodate excess lipids lies at the core of the metabolic syndrome (a major precursor of cardiovascular disease and cancer) that is paradoxically similar in both lipodystrophies and obesity.
A milestone of our research has been the description of Cav1 as a key regulator of the reciprocal biomechanical and biochemical crosstalk between stromal fibroblast and the extracellular matrix (ECM), which explains the central role of this protein in processes such as tumor stromal stiffening and subsequent invasion and metastasis, or tissue fibrosis and associated pathological cell reprogramming (Moreno-Vicente et al., Cell Rep 2018; Strippoli et al., EMBO Mol Med 2015; Goetz et al., Cell 2011). We have recently described that stromal Cav1 governs a novel route for the exosomal deposit of non-collagen ECM components, both locally and at distant locations (Albacete-Albacete et al., J Cell Biol). We aim to understand the physiopathological role of these processes for atherogenic arterial wall remodeling, myocardial regeneration after infarct-scar remodeling, and the potential of immune modulation for cardiovascular disease and cancer.
A major focus of our research is devoted to the structural, molecular and cell biology of caveolae—plasma membrane nanoscale invaginations abundant in mechanically challenged tissues (endothelium, muscle, adipose tissue)—and their main components, caveolins and cavins (del Pozo et al, Curr Op Cell Biol 2020; Echarri and Del Pozo J Cell Sci 2015; del Pozo and Parton, Nat Rev Mol Cell Biol 2013). Apart from allocating signaling modules and organizing membrane trafficking and structure, caveolae undergo reversible flattening upon PM tension increase, in a manner coordinated with actin cytoskeleton dynamics (Echarri et al, Nat Commun 2019; Minguet et al, Nat Immunol 2017; Muriel et al, J Cell Sci 2011; Echarri et al. J Cell Sci 2015 & 2012). We have developed different quantitative approaches to explore the molecular mechanisms governing the architecture and dynamic interactome of caveolae, with a particular interest on their changes during cell mechanoadaptation and their physical and functional contact with other structures in different cell types, such as endothelia, cardiomyocytes and adipocytes. The role of other molecular mechanisms driving cell membrane organization and mechanoadaption, such as Rac1 downstream signaling-driven actin-polymerization, is also studied (Navarro-Lérida et al., Dev Cell 2015 and EMBO J 2012).
A second research interest lies on charting the transduction signaling networks downstream cell mechanosensation, and understanding how they reprogram and coordinate different cell functions (secretion, contractility and motility, metabolism, inflammation) at systems level. We are studying novel molecular mechanisms regulating the YAP mechanotransduction system, which feeds from Cav1-dependent mechanosensing and actin cytoskeletal dynamics (Strippoli et al. Cell Death Diff 2020, Moreno-Vicente et al. Cell Rep 2018). We are also characterizing the role of different membrane trafficking regulators, including Cav1, on the differential responses of endothelial cells to atheroprotective fluid shear versus atherogenic disturbed patterns. Finally, we research the relevance of caveolae-dependent mechanotransduction in adipocytes for metabolic homeostasis: an insufficient physical capacity to expand and accommodate excess lipids lies at the core of the metabolic syndrome (a major precursor of cardiovascular disease and cancer) that is paradoxically similar in both lipodystrophies and obesity.
A milestone of our research has been the description of Cav1 as a key regulator of the reciprocal biomechanical and biochemical crosstalk between stromal fibroblast and the extracellular matrix (ECM), which explains the central role of this protein in processes such as tumor stromal stiffening and subsequent invasion and metastasis, or tissue fibrosis and associated pathological cell reprogramming (Moreno-Vicente et al., Cell Rep 2018; Strippoli et al., EMBO Mol Med 2015; Goetz et al., Cell 2011). We have recently described that stromal Cav1 governs a novel route for the exosomal deposit of non-collagen ECM components, both locally and at distant locations (Albacete-Albacete et al., J Cell Biol). We aim to understand the physiopathological role of these processes for atherogenic arterial wall remodeling, myocardial regeneration after infarct-scar remodeling, and the potential of immune modulation for cardiovascular disease and cancer.
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Journal of Experimental & Clinical Cancer Researchno. 1 (2024): 27-27
Laura Sotodosos-Alonso,Miguel A. del Pozo
Current Biologyno. 6 (2024): R244-R246
Cellsno. 6 (2023): 942-942
María C M Aboy-Pardal,Daniel Jimenez-Carretero, Sara Terrés-Domínguez,Dácil M Pavón,Laura Sotodosos-Alonso,Víctor Jiménez-Jiménez,Fátima Sánchez-Cabo,Miguel A Del Pozo
Jorge Alegre-Cebollada,Carla Huerta-Lopez, Alejandro Clemente-Manteca,Diana Velazquez-Carreras,Francisco M Espinosa,Pablo Saez,Alvaro Martinez-Del-Pozo,Maria Garcia-Garcia, Sara Martin-Colomo,Ricardo Garcia,Pere Roca-Cusachs,Alberto Elosegui-Artola,
Journal of materials chemistry. Bno. 39 (2023): 9431-9442
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Carla Huerta-Lopez, Alejandro Clemente-Manteca,Diana Velazquez-Carreras,Francisco M. Espinosa,Juan G. Sanchez,Pablo Saez,Alvaro Martinez-del-Pozo,Maria Garcia-Garcia, Sara Martin-Colomo, Andrea Rodriguez-Blanco, Ricardo Esteban-Gonzalez,Francisco M. Martin-Zamora,
biorxiv(2022)
María García-García,Sara Sánchez-Perales,Patricia Jarabo,Enrique Calvo,Trevor Huyton, Liran Fu,Sheung Chun Ng, Laura Sotodosos-Alonso,Jesús Vázquez,Sergio Casas-Tintó,Dirk Görlich,Asier Echarri,
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