KLF4 and Myeloid Cell Biology

描述(申请人提供)：代谢综合征(METS)是一组生化和生理紊乱的星座，困扰着全球近20%-25%的个人。人们越来越认识到，慢性炎症是一种统一的潜在机制，不仅对蛋氨酸代谢综合征的发生，而且对动脉粥样硬化性血栓心血管病的后续发展--这些人的发病率和死亡率的主要来源。最近的研究强调了单核/巨噬细胞系细胞在蛋氨酸综合征的发生及其后果(如动脉粥样硬化血栓形成)中的重要作用。单核/巨噬细胞系的细胞表现出显著的可塑性，使它们能够调节其表型，并有效地响应环境信号并改变其表型。为简单起见，开发了一个模型系统，将炎性巨噬细胞归类为M1，将抗炎巨噬细胞归类为M2巨噬细胞。这两个亚群的平衡被认为对生理和病理炎症反应有重要影响，但它们的形态和功能的分子决定因素仍然知之甚少。Kruppel样因子(KLFs)是一类锌指转录因子，参与包括造血生物学在内的多种生物学过程。尽管我们小组和其他人之前的研究表明KLF4与髓系细胞生物学有关，但在体内的生理相关性尚未阐明。根据我们的初步研究，KLF4在M2群体中的表达被鉴定为M2群体，而在M1巨噬细胞中的表达显著减少--这一观察结果在体内的人类炎症范例中得到了概括。功能获得和功能丧失研究表明，KLF4促进M2遗传程序并抑制M1靶基因。携带髓系特异性KLF4缺失的小鼠表现出典型的M1表型，杀菌活性增强。此外，作为对高脂饮食(HFD)的反应，这些动物产生了许多与蛋氨酸代谢综合征相一致的特征，包括肥胖、血脂异常、胰岛素抵抗和促动脉粥样硬化/血栓形成状态。这些观察结果为中心假设提供了基础，即KLF4是控制巨噬细胞亚群规格和功能的上游分子开关。为了更好地了解KLF4在巨噬细胞极化和功能中的确切作用，我们提出了三个目标。在目标1中，我们将描述KLF4在髓系细胞中表达的上游机制。在目标2中，我们将确定KLF4的S调节M1/M2表型的分子基础。在目标3中，研究将确定髓系KLF4表达改变对胰岛素抵抗和动脉粥样硬化血栓形成的影响。总之，这些研究将阐明KLF4介导的M2表型极化的分子基础，以及KLF4充足和缺乏在胰岛素抵抗和动脉粥样硬化血栓形成中的功能后果。 公共卫生相关性：巨噬细胞是机体对炎症反应的关键调节细胞，炎症导致胰岛素抵抗状态和动脉粥样硬化性血管疾病等疾病过程。我们小组最近的研究确定了一个调节巨噬细胞生物学关键方面的因素。这项提议试图了解该因子的潜在作用机制，目的是开发治疗炎症性疾病状态的新疗法。

DESCRIPTION (provided by applicant): The metabolic syndrome (MetS) is a constellation of biochemical and physical derangements that afflicts nearly 20-25% of individuals worldwide. It is increasingly appreciated that chronic inflammation is a unifying underlying mechanism not only for the development of MetS but also for the subsequent development of atherothrombotic cardiovascular disease - the primary source of morbidity and mortality in these individuals. Recent studies highlight an essential role for cells of the monocyte/macrophage lineage in the development of MetS and its consequences such as atherothrombosis. Cells of the monocyte/macrophages lineage exhibit remarkable plasticity that allows them to modulate their phenotype and efficiently respond to environmental signals and change their phenotype. For purposes of simplicity, a model system that classifies inflammatory macrophages as M1 and anti-inflammatory macrophages as M2 macrophages has been developed. The balance of these two subsets is thought to critically influence the physiologic and pathologic inflammatory response yet the molecular determinants of their speciation and function remain poorly understood. Kruppel-like factors (KLFs) are zinc-finger transcription factors implicated in a wide spectrum of biological processes including hematopoietic biology. Although previous studies by our group and others implicated KLF4 in myeloid cell biology, the in vivo physiological relevance has not been elucidated. Based on our preliminary studies, KLF4 expression is identified with the M2 population and strongly reduced in M1 macrophages - observations that are recapitulated in human inflammatory paradigms in vivo. Gain and loss-of-function studies reveal that KLF4 promotes an M2 genetic program and inhibits M1 target genes. Mice bearing myeloid-specific deletion of KLF4 exhibit a characteristic M1 phenotype as evidenced by enhanced bactericidal activity. Further, in response to a high fat diet (HFD), these animals develop numerous features consistent with MetS including obesity, dyslipidemia, insulin resistance, and a pro-atherogenic/pro-thrombotic state. These observations provide the foundation for the central hypothesis that KLF4 is an upstream molecular switch governing macrophage subset specification and function. To better understand the precise role of KLF4 in macrophage polarization and function, three aims are proposed. In Aim 1, we will delineate the upstream mechanisms governing KLF4 expression in myeloid cells. In Aim 2, we will determine the molecular basis for KLF4's ability to regulate the M1/M2 phenotype. In Aim 3, studies will determine the effect of altered myeloid KLF4 expression on insulin resistance and atherothrombosis. Collectively, these studies will elucidate the molecular basis for KLF4-mediated polarization towards the M2 phenotype and the functional consequences of KLF4 sufficiency and deficiency on insulin resistance and atherothrombosis. PUBLIC HEALTH RELEVANCE: The macrophage is a critical regulator of the body's response to inflammation that contributes to disease processes such as insulin resistant states and atherothrombotic vascular disease. Recent studies from our group have identified a factor that regulates key aspects of macrophage biology. This proposal seeks to understand the mechanisms underlying the function of this factor with the goal of developing novel therapies for the treatment of inflammatory disease states.