The proposed research plan is based on our documented findings that: (a) Compared to age-matched normal eyes, there is a qualitative increase in sialated moieties in the trabecular neshwork/Schlemm's canal (TM/SC) system of eyes with primary open-angle glaucoma. (b) The production of monoclonal antibodies to the TM/SC system is feasible, and the antibodies can provide valuable information on the antigenic determinants of the system. Specialized techniques of electron microscopy will be used for the demonstration of sialated moieties. We will analyze tissue specimens of the TM/SC system from normal human and monkey eyes, and from eyes of patients with a variety of glaucomatous conditions, including primary, secondary, congenital, and infantile glaucomas. We will perform quantitative morphometric analyses of these tissue samples under conditions representing those in vivo, and following maintenance of samples in organ or tissue culture. Emphasis is placed on electron histochemical and immunocytochemical techniques, and on the use of specific lectin markers for the demonstration of the sialic acid containing constituents of the surface of the endothelial cells lining the TM/SC system. As controls, the adjacent corneal endothelium, keratocytes, and scleral fibroblasts will be studied similarly. We will study the effect of corticosteroids and various antiglaucoma drugs on the extracellular sialated moieties. We also propose to investigate whether experimentally altered intraocular pressure influences the distribution of the sialated moieties of the endothelial cells. We have developed a small specific library of monoclonal antibodies that can recognize individual antigenic determinants of the macromolecules of the TM/SC system. Our plan is to expand this library in order to detect, isolate, and characterize disease-related epitopes as well as new or abnormal gene products in glaucomatous conditions. Overall, our objective in the proposed research is the use sensitive morphologic techniques, at the cellular and ultrastructural levels, and to generate monoclonal antibodies in order to probe the fundamental biology of the TM/SC system in normal and glaucomatous states of the eye. We anticipate that our investigations will result in a greater understanding of the pathophysiology of the cells of the TM/SC system. We believe that the results of this work will lead to new rational therapies, and perhaps even a cure, for glaucoma.
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