: The goal of this project is to gain an understanding of the regulation and biological roles of the members of the immediate lymphotoxin (LT)/tumor necrosis factor (TNF) family. These molecules contribute to inflammation through induction of chemokines and adhesion molecules. Individual ligands (LTalphax3, LTalpha1Beta2; TNFalpha) and receptors (TNFR1 and LTBetaR) play crucial and non-overlapping roles in development of lymph nodes, Peyer's patches, splenic organization, and nasal associated lymphoid tissue (NALT). Multiple different ligand receptor pairs interact to accomplish development of a full complement of lymphoid organs. A goal is to determine whether and how LT regulates development of high endothelial venules (HEV) and the switch in expression in peripheral lymph (PLN) HEV from mucosal addressin (MAdCAM-1) to peripheral node addressin (PNAd) in the perinatal period. Differences between LTalpha and LTBeta with regard to the NALT development and function will be studied as will the temporal and kinetic expression of LT and putative upstream and downstream genes and their interactions.
The specific aims are: I. Determination of LT' s role in mucosal immunity; II. Determination of the temporal and spatial regulation of LTalpha and LTBeta in development and determination of the cells of origin; III. Identification of upstream regulators of LT; IV. Identification of the downstream target genes of LT in development; V. Determination of the mechanism by which LT regulates downstream target genes.
These aims will be approached by evaluating NALT structure and function in mice deficient in the various LT/TNF family members; producing and evaluating expression of LT expression in embryogenesis and the perinatal and postnatal periods; monitoring expression of a reporter gene (Beta galactosidase or yellow fluorescent protein) knocked into the LTa locus; analyzing the role of Ikaros, a chromatin remodeling protein, in regulation of LTa and LTBeta with Ikaros knock-out and Ikaros. GFP reporter genes; evaluating LT family members in the regulation of lymphoid chemokines in pit mice and in the generation of the L-selectin ligand by the HEV sulfotransferase, HEC-GlcNAc6ST: and molecular characterization of HEV sulfotransferase regulation. Understanding the mechanisms of LT regulation of lymphoid organs in development will provide insight into common themes in inflammation and autoimmune disease and provide information for development of vaccines and identification of therapeutic targets.
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