Nuclear Receptors in Myeloid Development, Inflammation, and Atherosclerosis

描述(申请人提供)：NR4A1(Nur77)是一种孤儿核受体，其功能是作为转录因子调节炎症和细胞生存。NR4A1属于NR4A核受体家族，还包括NR4A2(Nurr1)和NR4A3(NOR-1)。NR4A1在单核细胞和巨噬细胞中表达，并在动脉粥样硬化病变中发现。我们在2011年发现，NR4A1是一种关键的转录因子，调节骨髓中Ly6C-单核细胞系的发育。Ly6C-单核细胞具有巡视血管系统的功能，从而启动快速的天然免疫反应。在这个建议中，我们假设NR4A1是骨髓中一个关键的转录因子，是Ly6C-单核细胞亚群增殖所必需的。此外，我们认为，巡逻单核细胞通过调节宿主防御和炎症反应来防止动脉粥样硬化的发展。我们有三个特定的目标：目标1将确定NR4A1是否通过调节细胞周期基因的表达来调节骨髓中单核细胞的产生和动态平衡。目的2将确定单核细胞中NR4A1的表达是否促进炎症的消退。目的3将确定体内缺乏巡逻的单核细胞是否促进动脉粥样硬化的进展。我们的发现揭示了NR4A1在调节骨髓祖细胞向单核细胞分化方面的新作用，这对包括动脉粥样硬化在内的多种炎症和免疫介导性疾病具有意义。由于单核细胞以TLR依赖的方式从骨髓中动员起来应对病原体，NR4A1在早期先天免疫反应中也可能在宿主防御中发挥重要作用。因此，确定NR4A1如何调节骨髓中单核细胞的产生及其对动脉粥样硬化的影响的机制具有非常重要的意义，因为这种NR4A类核受体可以作为药物靶向。

DESCRIPTION (provided by applicant): NR4A1 (Nur77) is an orphan nuclear receptor that functions as a transcription factor to regulate inflammation and cell survival. NR4A1 belongs to the NR4A family of nuclear receptors that also includes NR4A2 (Nurr1) and NR4A3 (NOR-1). NR4A1 is expressed in monocytes and macrophages and is found within atherosclerotic lesions. We discovered in 2011 that NR4A1 functions as a key transcription factor to regulate development of the Ly6C- monocyte lineage in bone marrow. Ly6C- monocytes possess patrolling functions to survey the vasculature to initiate rapid innate immune responses. In this proposal, we hypothesize that NR4A1 is a critical transcription factor in the bone marrow required for the proliferation of the Ly6C- monocyte subset. Furthermore, we propose that patrolling monocytes function to protect against atherosclerosis development by regulating host defense and inflammatory responses. We have 3 specific aims: Aim 1 will determine whether NR4A1 regulates the production and homeostasis of monocytes in bone marrow through regulation of cell cycle gene expression. Aim 2 will determine whether NR4A1 expression in monocytes promotes resolution of inflammation. Aim 3 will determine whether the absence of patrolling monocytes promotes atherosclerosis progression in vivo. Our discoveries reveal a novel role for NR4A1 in regulation of monocyte differentiation from bone marrow progenitors, which has implication for multiple inflammatory and immune-mediated diseases, including atherosclerosis. As monocytes are mobilized from bone marrow in response to pathogens in a TLR-dependent manner, NR4A1 may also play an important role in host defense during an early innate immune response. Thus, identifying mechanisms for how NR4A1 regulates monocyte production in bone marrow and its impact on atherosclerosis is highly significant, as this NR4A class of nuclear receptors can be targeted pharmacologically.