B 1ymphocytes are the central component of the humoral immune response and malignant B lymphocytes represent the primary cell type in leukemia and lymphoma Although B cells are activated and regulated through their cell- surface molecules, little is known about the structure and signal transduction pathways of most B cell-surface proteins other than immunoglobulin (Ig), Several B lymphocyte-restricted and -associated cell surface molecules have been identified that may serve critical roles in B lymphocyte function and adhesion with other cell types.
The aim of this project is to further examine the structure of several B cell surface molecules, CD19, CD20 and CD22 to determine their roles in B cell function. The first specific aim is to examine the structure, expression and function of the recently characterized CD19 signal-transducing complex present on B cells. CDI9 associates with a series-of other surface molecules to generate a functional signal generating.complex that includes CD21, TAPA-1, Leu-13 and additional uncharacterized proteins. The additional components of the complex will be identified and the structural requirements for complex formation will be determined. In addition, transgenic mice that express human CD19 have been generated that give rise to an abnormal phenotype. These mice will be used to characterize the struCture and function of both the human and mouse CD19 molecules and to further elucidate the mechanism of CD19 signal generation. CD19-deficient mice will also be produce by targeted disruption of the endogenous CD19 gene to further characterize the in vivo function of CD19. The second specific aim is to further examine the function of the B cell-specific CD20 molecule that regulates transmembrane Ca++ movement during B, lymphocyte cell cycle progression. CD20-deficient mice will also be produced by targeted disruption of thee endogenous CD20 gene. Mice that overexpress the human CD20 molecule on their 13 cells will also be produced to dissect the functional significance of CD20 in vivo and to determine what effect this has on normal Ca++ homeostasis and growth of B cells. The third specific aim is to further characterize the molecular basis for B cell adhesion through CD22. CD22 serves as a significant adhesion molecule for B lymphocytes that may also be important in cellular activation. In these studies, the receptor for CD22 will be identified-and it will be determined whether engagement of CD22 by this receptor has a functional effect on B cells. The roles of these proteins in B cell activation, proliferation, and differentiation will be examined. Determining the structural and functional characteristics of B cell- restricted proteins will provide a better understanding of how B cell function is regulated at the cell surface and may provide new methods for treatment of B cell malignancies and dysfunction.
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