The studies described in this proposal are designed to further our understanding of the function of leukocytes and platelets in health and disease. Most of the experiments will attempt to translate metabolic, biochemical and biophysical data into meaningful morphologic concepts. Thus we wish to determine what membrane changes occur when platelets adhere, aggregate or degranulate or how the integral membrane proteins lipids of lymphocytes are rearranged when the cells migrate or when they are stimulated into mitosis by a variety of means. Elucidation of the mechanism(s) of secretion, endocytosis and intracellular transport form part of the objective. Although the emphasis will be on surface membranes, intracellular proteins and organelles which play a role in specific cell functions will also be investigated. The methodologies will include conventional fluorescence and electron microscopy, cyto and immunohistochemistry on the light microscopic and ultrastructural level, freeze-fracture, cell fractionation and tissue culture. Specimens obtained from patients with abnormal platelet or leukocyte function will be compared with those obtained from healthy subjects and with cells which have been experimentally modified in vitro. The morphologic information derived from such studies seems important because, in the future, it may be possible to selectively alter structure, e.g., by insertion into membranes of missing molecules which may be essential for normal cell physiology. At all times, the ultimate goal is to help our understanding of aberrant blood cell function which is a prerequisite for the rational management of patients with hematologic disease.
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