Nuclear Receptors in Myeloid Development, Inflammation, and Atherosclerosis

描述（由申请人提供）：NR 4A 1（Nur 77）是一种孤儿核受体，作为转录因子发挥作用，调节炎症和细胞存活。NR 4A 1属于NR 4A核受体家族，该家族还包括NR 4A 2（Nurr 1）和NR 4A 3（NOR-1）。NR 4A 1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，NR 4A 1作为关键转录因子发挥作用，以调节骨髓中Ly 6C-单核细胞谱系的发育。Ly 6C-单核细胞具有巡逻功能以调查脉管系统以启动快速先天免疫应答。在这个提议中，我们假设NR 4A 1是骨髓中Ly 6C-单核细胞亚群增殖所需的关键转录因子。此外，我们提出巡逻单核细胞的功能，以防止动脉粥样硬化的发展，通过调节宿主的防御和炎症反应。我们有三个具体目标：目的1探讨NR 4A 1是否通过调控细胞周期基因的表达来调节骨髓单核细胞的生成和稳态。目的2将确定单核细胞中NR 4A 1的表达是否促进炎症的消退。目的3将确定巡逻单核细胞的缺乏是否促进体内动脉粥样硬化的进展。我们的发现揭示了NR 4A 1在调节骨髓祖细胞单核细胞分化中的新作用，这与多种炎症和免疫介导的疾病，包括动脉粥样硬化有关。由于单核细胞以TLR依赖性方式从骨髓动员以响应病原体，NR 4A 1也可能在早期先天免疫应答期间的宿主防御中发挥重要作用。因此，确定NR 4A 1如何调节骨髓中单核细胞产生及其对动脉粥样硬化的影响的机制是非常重要的，因为这种NR 4A类核受体可以靶向靶向细胞。

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.