Transplantation acceptance or rejection is determined by the cumulative effects of innate as well as adaptive responses to the foreign graft, however, the role of innate immunity in transplant rejection had been less studied than adaptive immunity. A focus on innate immunity is timely due to the discovery of Toll-like receptors (TLR's) in mammalian cells, which has revolutionized the field. The focus of this proposal is a member of a new family of genes called the CATERPILLAR family. Members are defined by shared motifs, including the caspase activation and recruitment domain (CARD), transcriptional enhancement domain, purine-binding domain, pyrin, and leucine rich domain. Others have also called this the NALP or NOD family. One of the CATERPILLAR genes, which we call Monarch-1, is only expressed by myeloid and monocytic cells. Its expression in primary monocytes is abrogated upon TLR activation through various agonists. When over-expression in non-monocytic/myeloid cell lines, Monarch-1 represses NF-kB/AP-1 activation. Thus it may be a negative regulator of inflammatory responses. In transplantation, negative regulators may be important for enhancing transplant acceptance. The goal fo this proposal is to further explore the role of Monarch-1 in myeloid/monocytic cells, and in cardiac and kidney transplant rejection.
The Aims are: (1) To produce a large number of myeloid-monocytic cell lines which lack Monarch-1 expression by the RNA interfenence (RNAi) technology. (2) To delineate the role of Monarch-1 in these cell lines in the activation of NF-KB and AP-1, in cytokine synthesis, and in overall gene expression profile. (3) To characterize Monarch-1 expression during kidney and cardiac transplantation. (4) To characterize the role of Monarch-1 in kidney and cardiac transplanttation by producing and using mice that lack the Monarch-1 gene.
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