Prof. Dr. Johannes Norgauer
Function of phosphatidylinositol-3-kinase-γ and SH2-containing inositol-5-phosphatase-1
in innate immunity.
Abstract:
Innate immunity refers to the activation of different antigen-nonspecific
mechanisms, including immune components as well as the non-immune
defense machinery. In this context, those cellular components of
the innate immune system are designed to recognize a few highly
conserved structures present in many different microorganisms, known
as pathogen-associated molecular patterns. Recent studies have illustrated
that γδ+ T cells and NK-T cells participate in natural immunity
alongside the classical cellular components such as neutrophils,
macrophages and NK cells. In leukocytes, chemotaxins activate phosphatidylinositol-3-kinase-γ
(PI3Kγ), which synthesizes phosphatidylinositol-3,4,5-trisphosphate
(PIP3). This lipid is further metabolized by SH2-containing inositol-5-phosphatase-1
(SHIP-1) to phosphatidylinositol-3,4-bisphosphate (PI3,4P2). Moreover
there is well evidence that PI3Kγ is also a protein kinase and functions
as an adaptor protein. The intention of this project is the comparative
study of upstream and downstream PI3Kγ/SHIP-1 signalling pathways
in γδ+ T cells and NK-T cells, in order to highlight the importance
of this cascade in the immune system. For this approach biochemical
analyses (e.g. phospholipid measurements and Akt, Rac, or Rho activation,
between other molecules), macrocomplex formation (e.g. immune precipitation,
lipid rafts experiments, mass spectrometry), cell studies (cytokine
production, growth factor release, secretion of matrix-metalloproteinases,
cytotoxicity) and animal experiments (e.g. infection with Escherichia
coli) will be performed in PI3Kγ-/- and SHIP-1-/- mice.
Our present proposal integrates different biological aspects. On
one side, it is related to the study of the innate immune, one of
the most important mechanisms necessary for the maintainance of
the life, since its main objective is to gain fundamental knowledge
about the 3-phospholipid metabolism in immune cells, in order to
better understand their patho- and physiological consequences. On
the other hand, PI3Kγ as well as SHIP represent, between others,
a novel feature into the classical protein field. These proteins,
as well as some of their downstream adaptors, show a high plasticity
due to their multifunctionality, e.g. acting as enzymes or adaptor
proteins, which allows a larger range of pharmacological intervention
strategies, in order to modulate the immune reactions, as well as
other biological processes.
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