Extracellular matrix (ECM) macromolecules which play significant structural roles in maintaining tissue integrity, also appear to have dramatic effects on the behavior of specific cells during morphogenesis and tissue remodeling. This proposal focuses on one such ECM macromolecule, the nonsulfated glycosaminoglycan, hyaluronic acid (hyaluronate, HA) and the enzymes involved in its turnover, with specific emphasis on a hyaluronidase (of presumptive lysosomal origin) which preferentially degrades HA. Despite many correlative studies in developing and remodeling tissues, neither the mechanism by which HA influences cell behavior nor the manner in which cells regulate HA levels is well understood. This proposal aims to answer these question using a combined biochemical/immunochemical approach, coupled with a series of biological studies. These include the purification of hyaluronidase and preparation of specific anti-hyaluronidase monoclonal antibodies for use i. in in situ localization studies; ii. in experimental manipulations of HA levels and subsequent observation of biological effects; iii. for immunohistochemical studies of specific developing tissues; and iv. ultimately for molecular biological approaches to the study of the hyaluronidase gene and its regulation during development. Biological studies aim to determine the relationship of HA size to turnover and to its biological influences, as well as to determine if the molecular weight of HA is developmentally regulated. Specific tissues to be examined include differentiating skeletal muscle, embryonic cardiac cushion tissue, and cells of the vessel wall. Since HA and hyaluronidase are currently in use therapeutically for a wide range of purposes, from intraocular surgery to treatment of myocardial infarction, an understanding of the biological effects of this macromolecule and the manner in which cells metabolize it is not only of fundamental interest, but of current practical concern as well.
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