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

描述（由申请人提供）：本项目的长期目标是评估造血干细胞（HSC）在机体对感染的反应中的作用。干扰素-γ（IFN-γ）途径调节宿主对病原体的应答，并且途径成员如IFNGR 1、IFNGR 2和STAT 1的突变与人类免疫缺陷有关。IFN-γ信号传导诱导许多下游靶标，包括GTP酶的p47家族。LRG-47是鼠p47家族的成员，对于宿主对细胞内细菌和原生动物的应答至关重要。骨髓移植和集落形成试验表明，LRG-47也是HSC功能所必需的。此外，在人类同源LRG- 47，IRGM序列变异，最近牵连克罗恩病，表明其失调可能会导致过度活跃的免疫反应。因此，LRG-47似乎是一个重要的参与者，可以定义免疫损伤，IFN-γ信号传导和HSC反应之间的联系。因此，有必要通过检查LRG-47在HSC中的活性、其在IFN-γ途径中的作用以及进一步研究其下游靶点来进一步确定LRG-47的功能。为了表征HSC中的LRG-47，将检查其在细胞周期控制中的作用。此外，拯救Lrg-47-/-HSC的移植表型的实验将鉴定LRG-47与其人和鼠同源物之间的功能重叠。将评估IFN-γ对HSC区室的体内作用，以及LRG-47表达对IFN途径的依赖性。最后，一组IFN相关基因可能受LRG-47调控;这些基因将作为可能的LRG- 47靶点进行检查。在这些基因中，Ifit家族特别有趣，因为最近发现人类IFIT 1在系统性红斑狼疮中发挥作用。如果家庭成员将被击倒，以研究他们在造血中的重要性。对这些基因在免疫应答和HSC中的作用的进一步理解可能会为自身免疫性疾病和免疫缺陷提供深入了解。相关性：造血干细胞（HSC）是一种干细胞，可以产生血液中所有不同的细胞，包括免疫细胞，其正常功能对于身体对感染的反应至关重要。如果HSC没有得到正确的调节，那么身体的免疫系统就会出现缺陷，要么无法保护身体免受感染，要么以自身免疫性疾病的形式攻击身体自身的组织。通过研究HSC调节与免疫反应之间的关系，可以深入了解这些通常危及生命的疾病，这可能会导致未来更好的治疗方法。

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.