Hyaluronic acid (HA) is a ubiquitous component of the extracellular matrix in higher organisms. HA is important during embryonic development and in differentiated tissues for a wide range of normal cellular functions including cell adhesion, migration, vascularization and morphogenesis. Alterations in the interaction between HA and cells are associated with pathogenic or abnormal conditions such as arthritis, Marfan's syndrome, tumorigenesis and metastasis. The long range objective of this proposal is to define the molecular mechanisms by which cells respond to and utilize HA in the matrix to perform these various functions. We have developed several uniquely modified HA derivatives which have allowed us to prepare 125I-HA of high specific activity, HA-Sepharose for affinity purification of HA receptors and synthetic cell culture surfaces containing covalently attached HA. We propose to use these new research tools (i) To examine a wide range of different cell types for the presence of specific cell surface receptors for HA. A smaller number of representative cell types will be studied further to characterize and, where possible, to purify these receptors. (ii) To assess the behavior on HA culture surfaces of several cell types, which express HA receptors. A hierarchical range of possible cellular responses will be examined including binding, spreading, rate of growth, saturation density, migration and contact inhibition of growth and motion. (iii) To characterize the molecular interaction between the cell surface and the HA culture surface during their initial interaction. The possibility that HA attached to the substratum can be modified by cells, or cell products, will also be tested. These studies will determine the distribution and generality of cellular HA receptors among a wide variety of cell types and the ability of cells to use such receptors to respond to immobilized HA in the extracellular environment.
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