Protein kinase C (PKC)-induced phosphorylation in macrophages is necessary for a full functional response to bacterial lipopolysaccharides (LPS).
The aim of this research is to investigate the mechanism by which PKC-dependent signaling pathways modulate membrane traffic events related to the immune response to infectious agents. Our focus is the molecular characterization of the MacMARCKS protein, an LPS-inducible PKC substrate, which is associated with vectorial membrane movement in macrophages. We will characterize phagocytosis, endocytosis, and antigen presentation in macrophages isolated from MacMARCKS null (knockout) mice, and from transgenic mice which express a dominant negative MacMARCKS transgene. Parallel studies will done in macrophage-like cell lines which stably express mutant forms of MacMARCKS. PKC-dependent phosphorylation, and LPS, regulate the movement of MacMARCKS between intracellular compartments including phagosomes, lysosomes, and endosomes. We will define the signals which target MacMARCKS to each of these compartments and identify the protein """"""""receptors"""""""" to which they bind. We have identified an LPS response element (LRE) in the 5' upstream region of the MacMARCKS promoter. The LRE will be characterized, and trans-acting factors will be identified with the ultimate goal of reconstructing the LPS signal transduction pathway from the plasma membrane to the nucleus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI032972-05
Application #
2067920
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1992-07-01
Project End
2000-06-30
Budget Start
1996-04-01
Budget End
1996-06-30
Support Year
5
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
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