The goal of the protect is to understand the motor mechanism utilized by blood cells involved in defense against infection and in hemostasis to move, participate in blood coagulation, ingest particulate objects and secrete bioactive mediators. An understanding of this mechanism may enable physicians in the future to modify these functions and thereby improve host defense or hemostasis, diminish inflamation, anticoatulate therapeutically and influence the invasive behavior of malignant blood cells. The region of blood cells responsible for these functions is the peripheral (cortical) cytoplasm. Accordingly, the research has concerned an analysis of the molecules comprising cortical cytoplasm, principally actin and actin-associated proteins. Progress with the project over 14 years has provided good evidence that actin-binding protein (ABP) is responsible for the branching of actin filaments in cortical cytoplasm and that the linear assembly of monomeric actin into filaments in the presence of ABP is sufficient to generate a 3-dimensional network resembling cortical cytoplasm. This proposal, therefore, emphasizes studies on the regulation of macrophage and platelet actin assembly in reponse to signals generated by cell stimulation acting on actin- assembly-modulating proteins.
The specific aims are to: 1. understand better the biochemistry of recently discovered regulation of gasoline by polyphosphoinositides (ppIs) in vitro; 2. follow leads suggesting a broader than heretofore suspected repertoire of actin regulation in blood cells by examining the interaction of gasoline and cell membranes in vitro, enzymatic effects of profiling or other agents on actin assembly in macrophage extracts, the nature of """"""""pointed"""""""" actin-filament end nucleating activity in macrophage extracts; 3. to see if actin/gasoline complexes form in phagocytosing macrophages under calcium-depleted conditions and if gasoline/calcium-reservoir association exists in the macrophage; 4. determine the effects of genetically engineered alterations in profiling and gasoline expression and of expression of a profiling-binding compound in myeloid cells on the motile functions of undifferentiated and differentiated myeloid cell lines.
| Yang, Zhiping; Chiou, Terry Ting-Yu; Stossel, Thomas P et al. (2015) Plasma gelsolin improves lung host defense against pneumonia by enhancing macrophage NOS3 function. Am J Physiol Lung Cell Mol Physiol 309:L11-6 |
| Nakamura, Fumihiko; Stossel, Thomas P; Hartwig, John H (2011) The filamins: organizers of cell structure and function. Cell Adh Migr 5:160-9 |
| Kasza, K E; Broedersz, C P; Koenderink, G H et al. (2010) Actin filament length tunes elasticity of flexibly cross-linked actin networks. Biophys J 99:1091-100 |
| Koenderink, Gijsje H; Dogic, Zvonimir; Nakamura, Fumihiko et al. (2009) An active biopolymer network controlled by molecular motors. Proc Natl Acad Sci U S A 106:15192-7 |
| Nakamura, Fumihiko; Heikkinen, Outi; Pentikainen, Olli T et al. (2009) Molecular basis of filamin A-FilGAP interaction and its impairment in congenital disorders associated with filamin A mutations. PLoS One 4:e4928 |
| Kasza, K E; Nakamura, F; Hu, S et al. (2009) Filamin A is essential for active cell stiffening but not passive stiffening under external force. Biophys J 96:4326-35 |
| Nakamura, Fumihiko; Osborn, Teresia M; Hartemink, Christopher A et al. (2007) Structural basis of filamin A functions. J Cell Biol 179:1011-25 |
| Weins, Astrid; Schlondorff, Johannes S; Nakamura, Fumihiko et al. (2007) Disease-associated mutant alpha-actinin-4 reveals a mechanism for regulating its F-actin-binding affinity. Proc Natl Acad Sci U S A 104:16080-5 |
| Gardel, M L; Nakamura, F; Hartwig, J H et al. (2006) Prestressed F-actin networks cross-linked by hinged filamins replicate mechanical properties of cells. Proc Natl Acad Sci U S A 103:1762-7 |
| Gardel, M L; Nakamura, F; Hartwig, J et al. (2006) Stress-dependent elasticity of composite actin networks as a model for cell behavior. Phys Rev Lett 96:088102 |
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