The broad, long term objective of this proposal is to understand the role of adhesion molecules in the pathogenesis of lymphoid malignancies. This proposal will focus on the regulatory and functional mechanisms of integrins that control cell adhesion and the processes of cell migration and localization. The major hypotheses of this proposal are (1) although levels of integrin expression have obvious implications in the development of cancer, it is the alterations in the regulation of integrin receptor function that result in the major pathophysiological consequences, and (2) unique regulatory alterations will characterize distinctly differentiated normal lymphocyte subpopulations and malignant lymphocytes with different histopathological sybtypes and grades. The major observations that provide much of the foundation of this proposal are (1) integrin-mediated adhesion of lymphoid cells is subject to a regulatory cycle of """"""""off"""""""" and """"""""on"""""""" signals, (2) integrin triggering induces the rapid morphological changes in lymphocytes that result in pseudopodial extension and motility, and (3) normal resting lymphocytes, normal activated lymphocytes, indolent non-Hodgkin's lymphoma cells, chronic lymphocytic leukemia, and acute lymphoblastic leukemia cells all apparently have different alterations in these processes.
The specific aims will employ a combination of quantitative cellular adhesion and spreading assays, digital color microscopy, biochemical assays, and immunochemical techniques to analyze the roles of different structural and signal transduction molecules in the initiation and maintenance of integrin-mediated adhesion, pseudopodial extension, and transendothelial migration. The health relatedness of this research is that an understanding of normal integrin regulation versus that found in disease states and function may have diagnostic or prognostic value to the clinician and will lay the foundation for the development of novel therapeutic methods for controlling the growth and metastasis of leukemia and lymphoma cells, potentially allowing normal integrin functions to be maintained.
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