LRG-47: a critical regulator of host defense and hematopoietic stem cell function

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DESCRIPTION (provided by applicant): The long-term objective of this project is to assess the role of the hematopoietic stem cell (HSC) in the body's response to infection. The interferon-gamma (IFN-v) pathway regulates the host response to pathogens, and mutations in pathway members such as IFNGR1, IFNGR2 and STAT1 have been implicated in human immunodeficiencies. IFN-y signaling induces many downstream targets, including the p47 family of GTPases. LRG-47, a member of the murine p47 family, is critical for host response to intracellular bacteria and protozoa. Bone marrow transplants and colony-forming assays demonstrated that LRG-47 is also essential for HSC function. Moreover, a sequence variant in the human homologue of LRG- 47, IRGM, was recently implicated in Crohn's disease, suggesting its dysregulation may cause ahyperactive immune response. LRG-47 thus appears to be a vital player that may define the connection between immune insult, IFN-y signaling and HSC response. Therefore, it is necessary to further define LRG-47 function by examining its activity in the HSC, its role in the IFN-y pathway, and further investigating its downstream targets. To characterize LRG-47 in the HSC, its role in cell cycle control will be examined. Additionally, experiments to rescue the engraftment phenotype of Lrg-47-/- HSCs will identify functional overlap between LRG-47 and its human and murine homologues. The in vivo effect of IFN-y on the HSC compartment will be assessed, as will the dependence of LRG-47 expression on the IFN pathway. Finally, a set of IFN-related genes is potentially regulated by LRG-47; these genes will be examined as possible LRG- 47 targets. Of these genes, the Ifit family is especially interesting as human IFIT1 was recently found to play a role in systemic lupus erythematosus. Ifit family members will be knocked-down to study their importance in hematopoiesis. Improved understanding of the role of these genes in the immune response and in the HSC may provide insight into autoimmune diseases as well as immunodeficiencies. Relevance: The hematopoietic stem cell (HSC) is a stem cell which gives rise to all of the different cells of the blood, including immune cells, and its proper function is essential for the body's response to infection. If the HSC is not correctly regulated, then the body's immune system will be defective either by failing to defend the body from infection, or by attacking the body's own tissues in the form of an autoimmune disease. By studying the relationship between HSC regulation and the immune response, insight may be gained into these often life-threatening diseases, which can lead to better therapies in the future.