Cel Sepsis, the systemic inflammatory host response to infection, is a major health problem. Inflammation is considered the first line of defence in host-pathogen interactions. Granzymes (grzs) are a family of proteases released from secretory granules that have been suggested to have relevant effects in inflammation. Outstanding findings are the rationale to hypothesize that granzymes play an essential role in the host response to bacterial sepsis: various bacteria can induce release of GrzA and B by leukocytes; elevated plasma levels of GrzA and B have been found in patients with sepsis; intravenous injection of LPS into healthy humans is a potent inducer of GrzA and B; deficient mice in GrzA and M are resistant to LPS-induced systemic inflammation and lethality; and GrzA-deficient mice show an improved host defence during pneumonia caused by S. pneumoniae.The aim of the proposed project is to determine the role of GrzA, B and M in host response to bacterial sepsis, studying which cells produce them and via which receptors this production is induced, and what their function is during sepsis. For this purpose, we will use mouse models of sepsis, pneumonia and peritonitis (the most common causes of sepsis) and human subjects from the Intensive Care Unit with and without sepsis and healthy controls. We will determine grzs producing cell types and grzs plasma levels both in humans and mice. We will examine the role of Toll-like receptors (TLR) in the bacterial induction of grzs in splenocytes from TLR-deficient mice incubated with relevant bacteria, and then compare grzs expression of wild-type and TLR-deficient mice with sepsis. Finally, grz-deficient mice will be compared with normal wild-type mice with regard to key host responses during pneumonia, peritonitis or primary sepsis.This project will provide in depth information on the regulation of grzs production during sepsis and their contribution to the host response during severe bacterial infection. Dziedzina nauki medical and health sciencesclinical medicinepneumologynatural sciencesbiological sciencesmicrobiologybacteriologymedical and health sciencesclinical medicinecritical care medicine Program(-y) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Temat(-y) FP7-PEOPLE-2011-IEF - Marie-Curie Action: "Intra-European fellowships for career development" Zaproszenie do składania wniosków FP7-PEOPLE-2011-IEF Zobacz inne projekty w ramach tego zaproszenia System finansowania MC-IEF - Intra-European Fellowships (IEF) Koordynator ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM Wkład UE € 247 199,80 Adres MEIBERGDREEF 15 1105AZ Amsterdam Niderlandy Zobacz na mapie Region West-Nederland Noord-Holland Groot-Amsterdam Rodzaj działalności Higher or Secondary Education Establishments Kontakt administracyjny Tom Van Der Poll (Prof.) Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Koszt całkowity Brak danych
