Team Laura Brion
Live imaging of vesicles containing EGFP- tagged Na,K-ATPase a-subunits (orange) along microtubules (microinjected fluorescent tubulin-green) in renal epithelial cells (size bar 50 um).
Signaling networks integration in cardiovascular diseases
Our mission is to understand cellular mechanisms behind the translation of receptor signals and their integration into signaling networks. Achieving temporal and spatial organization between receptor pathways and effectors is essential for reaching specificity and for avoiding deletereous crosstalk. Major goals are to better define mechanisms of disease that could lead to reliable therapeutic approaches within the areas of hypertension and cardiovascular complications.
Signal transduction is the molecular basis for cellular communication. Complex networks of intracellular molecules enable cells to receive signals from their environment and to modify their behavior in response to these signals. Signaling molecules are interconnected, and depending on how they are linked together they can form different types of networks. We have recently described a novel network of proteins that becomes activated by increases in cell sodium permeability and that regulates active sodium transport. Because each component of this sodium-sensing network so far described have been independently associated with multiple and essential cell functions, our work on the network topology and modeling is of importance because it will help us to understand the network’s role and complexity when transforming the sodium signal into transcription activation and gene expression leding to changes in myocardial- and/or renal cells growth.
Also, understanding the function and relevance of the cell sodium sensing network is of paramount importance for unraveling basic principles of animal cells’ evolution regarding their control of water and solute homeostasis. The latter constitutes a universal and essential mechanism for the cells to cope with a constant osmotic stress (and consequently risks of flooding and death) and, in evolutionary terms, permitted other functions to develop and cells to differentiate into superior organisms.
Our strategy combines in vitro studies as well as studies in human and animal models of disease, providing a unique opportunity to asses in an integrated manner the potential role of a new target network during disease’s development. The relevance and impact of the sodium-sensing network is assessed from different angles, including genetics, biochemistry, molecular cell biology/physiology and imaging. The hierarchical organization and structural dynamics of the sodium-networks are also assessed using live imaging techniques and mathematical network modeling.
Despite advances in treatment strategies, high blood pressure still results in an increased risk of death from coronary heart disease, stroke, renal failure and vascular disease. The prognosis is negatively affected when further associated with diabetes or obesity. Remarkable progress has been made in the diagnosis and treatment of heart disease. However, and despite these advances, cardiovascular diseases remain the most common fatal and disabling disorders that highlight the need for research on etiology, pathogenesis, prevention, diagnosis, and treatment.
Increased knowledge within cardiovascular physiology is a prerequisite for advances in etiology and pathogenesis of disease. A central aspect in studying the molecular and cellular aspects of cardiovascular physiology encompasses the study of cell membrane physiology, including membrane receptors, the function of membrane transport proteins, and signal transduction mechanisms, in order to determine how dysregulation of these mechanisms might result in the development of disease, and to identify potential molecular targets for treatment.
The ultimate goals within the area of cardiovascular cell physiology and signal transduction are to understand the normal behavior and the alterations that occur in the renal epithelia, the vasculature and cardiac myocytes in response to various stresses such as high salt-diet, metabolic perturbations and hypertension.
Jacob I. Sznajder, Professor and Chairman, Pulmonary and Critical Care Unit, Department of Medicine, Northwestern University, Chicago, IL, USA
Naoki Mochizuki, Professor and Chairman, Department of Structural Analysis, National Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka 565-8565, Japan.
Hiroshi Takemori, Group Leader, Laboratory of Cell Signaling and Metabolism, National Institute of Biomedical Innovation, Project 6, 7-6-8, Asagi, Saito, Ibaraki, Osaka, Japan
Per Eriksson, Professor and Head, Atherosclerosis Research Unit, Cardiovascular Genetics, Department of Medicine, Karolinska Institutet, Karolinska University Hospital-Solna, Stockholm, Sweden
Patricio Soares-da-Silva, Professor and Chairman, Institute of Pharmacology & Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal.
NATIONAL & INTERNATIONAL RESEARCH GRANTS AS PROJECT LEADER (FROM 2005)
ACTIVE: 1- Principal Investigator, Swedish Research Council, 01/01/11-31/12/13; 2- Principal Investigator, Swedish Heart & Lung Association, 01/01/10-31/12/12; 3- Principal Investigator, AFA Insurance, 01/08/10-31/07/13; 4- Co-Investigator (6% effort), National Heart, Lung, and Blood Institute, USA, RO1-HL48129-14:4/1/08-3/31/13.
Laura Brion Post-doctor Fellow, Team Leader
Edgar Jaramillo Martinez, Senior Physician-Scientist