Immune recognition relies on the ability of immunoglobulins and cell surface receptors to recognize foreign antigens without injuring self. Lymphocytes acquire this specificity during their maturation. Therefore, understanding the control of these developmental processes may provide insights into disease states that result from dysregulation of lymphocyte function. The Notch family of transmembrane receptors (which include Notch 1,2,3 and 4), originally described in Drosophila melanogaster, have been shown to significantly influence mammalian T lymphocyte development and positive selection. They are expressed in high levels in developing B lymphocytes suggesting they may also control B lymphopoiesis. The overall goal of this proposal is to determine the role of Notch family members in B lymphocyte development and differentiation. As with other ubiquitously expressed developmental proteins, Notch gene disruption studies have resulted in lethal mutations. Therefore, either dominant-negative or activated forms of the Notch 2 protein will be expressed as a transgene during B lymphopoiesis.
The specific aims are: (1) To direct expression of a constitutively- activated or dominant-negative Notch2 in B lymphocytes during lymphopoiesis in mice, (2) To define the phenotypic alterations cause by manipulations of Nothc2 activity during B lymphocyte development, and (3) To characterize, using DNA array, the effects of Notch 2 activation on gene expression in developing B lymphocytes.
These specific aims will test the hypothesis that the Notch2 transmembrane receptor directs differentiation of B lymphocyte during the development. Knowledge gained from these studies will provide insights into the control of normal lymphocyte maturation that may be of clinical import in understanding cellular aspects of solid organ graft rejection.
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| Kuhr, Christian S; Allen, Margaret D; Junghanss, Christian et al. (2002) Tolerance to vascularized kidney grafts in canine mixed hematopoietic chimeras. Transplantation 73:1487-92 |
