Septic shock is a majorcause of mortality in intensive care units and it’s often associated with encephalopathy that has been associated to poorer outcome in survivors. Alterations of the blood-brain barrier (BBB) could favour the entry of pro-inflammatory mediators and neurotoxic molecules. MRI studies confirm the presence of vasogenic oedema in septic shock patients. However, alterations of the BBB remain to be confirmed, reproduced and understood in more depth in animal models that more closely mimic human sepsis.
Our hypotheses are the following: during sepsis
• early modification of cerebral blood flow regulation is linked to the (peri)vascular production of vasoactive mediators (prostaglandins, nitric oxide, serotonin).
• physical disruption of the BBB results in an increased permeability for neurotoxic molecules and initially occurs as a consequence of the action of pro-inflammatory mediators.
• further increased cellular permeability of the BBB occurs as a consequence of endothelial expression of adhesion molecules (ICAM-1, VCAM-1) and subsequent transcellular migration of circulating leukocytes into nervous tissue as well as sustained activation of microglial cells.
Then we will study:
• fine alterations of the BBB during sepsis in both human and animal material using immunohistochemistry and 3D reconstruction of the different cellular and molecular components
• regulation of cerebral endothelial permeability to (i) solutes (trans and paracellular diffusion) and (ii) cellular elements, including leukocytes and pathogenic microorganisms (trans- et para-endothelial cellular migration) as well as (iii) the expression of transporter, tight junction proteins (occludin, claudins, JAMs) and adhesion molecules (VCAM-1, ICAM-1, CD44) in organotypic cultures of the BBB and reconstituted models exposed to septic conditions.
Because collaboration with hospitals, we dispose of a unique brain bank (already available) of patients that have died from septic shock with or without neurological complications (Sharshar et al., 2004 ; Sonneville et al., 2009) as well as of animal and cellular models to study alterations of cerebral blood flow and the BBB in conditions mimicking sepsis.
We offer a one year post-doctoral position (with the possibility of extension to two years) in Paris in Institut Pasteur in the unit “Human histopathology and animal models” headed by Fabrice Chrétien MD, PhD.
This position is open for a German citizen with her/his PhD completed. Cell culture as well as animal model experiences are required.
Please send your curriculum vitae and a motivation letter to eval(unescape('%64%6f%63%75%6d%65%6e%74%2e%77%72%69%74%65%28%27%3c%61%20%68%72%65%66%3d%22%6d%61%69%6c%74%6f%3a%66%61%62%72%69%63%65%2e%63%68%72%65%74%69%65%6e%40%70%61%73%74%65%75%72%2e%66%72%22%3e%66%61%62%72%69%63%65%2e%63%68%72%65%74%69%65%6e%40%70%61%73%74%65%75%72%2e%66%72%3c%2f%61%3e%27%29%3b'))
Application Deadline 1October2010