Based on our previous and ongoing studies, fibronectin (FN) - a multifunctional dimeric glycoprotein in plasma, basal lamina, and connective tissue matrices - participates in host defense, maintenance of lung architecture, and collagen deposition. These multiple biologic roles are possible by virtue of FN binding via specific sites or domains to other structural macromolecules, to itself, and to receptor armed cells. While this general scheme is well established, the cellular and molecular basis of FN's interactions with cells and with connective tissue components is not presently understood, but is critical for elucidating FN's role in lung structure and function. We have developed and applied new methods over the past three years, including a library of domain specific anti-FN antibodies and fragments with defined biologic activity, as well as biochemical and morphologic techniques to critically evaluate the basis of FN's interactions with cells and organization of connective tissue matrices. These methods will now be applied to the following specific aims: 1) The role of FN in supramolecular organization and deposition of other pericellular matrix components, including collagen and glycosaminoglycans in fibroblast culture. 2) The mechanisms of pericellular matrix organization in fibroblast cultures. 3) The interaction of FN with cells in two contrasting models: the human alveolar macrophage, and cultured lung fibroblasts, using antibodies to the FN cell receptor and heterologous mixing experiments to determine the requirements for extracellular matrix formation by FN secreting cells. Together, our studies will lead to new knowledge and tools fundamental to understanding the basis of FN's biological activities, and help to clearly delineate FN's role in lung and other organ structure and function. This information will provide a rational basis for diagnostic and ultimately theraputic intervention in lung and other diseases characterized by abnormal organization of connective tissue matrices. A promising first step in this direction is our ability to inhibit collagen deposition in lung fibroblast cultures by selective inhibition of FN matrix formation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM038276-03
Application #
3294538
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1986-08-01
Project End
1989-07-31
Budget Start
1987-08-01
Budget End
1988-07-31
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Wu, C; Chung, A E; McDonald, J A (1995) A novel role for alpha 3 beta 1 integrins in extracellular matrix assembly. J Cell Sci 108 ( Pt 6):2511-23
Simon, E E; Liu, C H; Das, M et al. (1994) Characterization of integrins in cultured human renal cortical tubule epithelial cells. Am J Physiol 267:F612-23
Roman, J; McDonald, J A (1993) Fibulin's organization into the extracellular matrix of fetal lung fibroblasts is dependent on fibronectin matrix assembly. Am J Respir Cell Mol Biol 8:538-45
Wu, C; Bauer, J S; Juliano, R L et al. (1993) The alpha 5 beta 1 integrin fibronectin receptor, but not the alpha 5 cytoplasmic domain, functions in an early and essential step in fibronectin matrix assembly. J Biol Chem 268:21883-8
McDonald, J A (1991) Applications of cell and molecular biology to pneumonology. Schweiz Med Wochenschr 121:89-95
Limper, A H; Quade, B J; LaChance, R M et al. (1991) Cell surface molecules that bind fibronectin's matrix assembly domain. J Biol Chem 266:9697-702
McDonald, J A (1991) Idiopathic pulmonary fibrosis. A paradigm for lung injury and repair. Chest 99:87S-93S
Simon, E E; McDonald, J A (1990) Extracellular matrix receptors in the kidney cortex. Am J Physiol 259:F783-92
Roman, J; LaChance, R M; Broekelmann, T J et al. (1989) The fibronectin receptor is organized by extracellular matrix fibronectin: implications for oncogenic transformation and for cell recognition of fibronectin matrices. J Cell Biol 108:2529-43
McDonald, J A (1989) Receptors for extracellular matrix components. Am J Physiol 257:L331-7

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