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

描述(由申请人提供)：该项目的长期目标是评估造血干细胞(HSC)在人体对感染的反应中的作用。干扰素-γ(IFN-v)途径调节宿主对病原体的反应，途径成员如IFNGR1、IFNGR2和STAT1的突变与人类免疫缺陷有关。干扰素-γ信号诱导了许多下游靶点，包括P47家族的GTP酶。LRG-47是小鼠P47家族的成员，在宿主对细胞内细菌和原生动物的反应中起关键作用。骨髓移植和集落形成实验表明，LRG-47对HSC的功能也是必不可少的。此外，人类LRG-47同源物中的一个序列变体IRGM最近被发现与克罗恩病有关，这表明它的失调可能导致免疫反应过度活跃。因此，LRG-47似乎是一个重要的角色，它可能定义了免疫损伤、干扰素-γ信号和HSC反应之间的联系。因此，有必要通过检测LRG-47在肝星状细胞中的活性、在干扰素-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。为了确定LRG-47在HSC中的特征，我们将研究它在细胞周期控制中的作用。此外，挽救LRG-47-/-HSCs植入表型的实验将确定LRG-47与其人和小鼠同源物之间的功能重叠。将评估干扰素-γ对HSC间隔室的体内作用，以及LRG-47表达对干扰素途径的依赖。最后，一组与干扰素相关的基因可能受到LRG-47的调控；这些基因将作为LRG-47的可能靶标进行研究。在这些基因中，iFit家族尤其令人感兴趣，因为最近发现人类ifit 1在系统性红斑狼疮中发挥了作用。IFit家庭成员将被击倒，以研究它们在造血中的重要性。更好地了解这些基因在免疫反应和HSC中的作用可能有助于深入了解自身免疫性疾病以及免疫缺陷。相关：造血干细胞(HSC)是一种干细胞，能产生血液中所有不同的细胞，包括免疫细胞，其适当的功能对身体对感染的反应至关重要。如果HSC没有得到正确的调控，那么人体的免疫系统就会出现缺陷，要么无法保护身体免受感染，要么会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调节和免疫反应之间的关系，可以深入了解这些经常危及生命的疾病，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.