Role of KLF6 in myeloid cell biology

KLF6 在骨髓细胞生物学中的作用

• 批准号: 8910985
• 负责人: Ganapati Holanagadde Mahabaleshwar
• 金额: $ 39.63万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8910985
• 关键词: Acute; Address; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Atherosclerosis; Attenuated; Autoimmune Diseases; Bacterial Infections; Biology; Body fat; Cell physiology; Cells; Cellular biology; Chronic; Clinical; Complication; Development; Diabetes Mellitus; Diet; Disease; Equilibrium; Event; Family; Fatty acid glycerol esters; Figs - dietary; Foundations; Gene Expression; Glucose Intolerance; Health; Healthcare; Human; Immune response; Infection; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Interferon Type II; Interleukin-4; Interleukin-6; Kruppel-like transcription factors; Mediating; Metabolic syndrome; Molecular; Molecular Target; Morbidity - disease rate; Myelogenous; Myeloid Cells; Obesity; Pathologic; Pathologic Processes; Patients; Peroxisome Proliferator-Activated Receptors; Phase; Physiological; Process; Production; Regulation; Regulatory Pathway; Resolution; Role; Sepsis; Sepsis Syndrome; Signal Pathway; Site; Stimulus; TNF gene; Therapeutic; Tissues; Transcriptional Regulation; United States; Zinc Fingers; angiogenesis; arginase; base; cellular development; cytokine; dectin 1; gene function; human disease; in vivo; interest; loss of function; macrophage; mannose receptor; member; mortality; novel; research study; response; septic; transcription factor; tumor

DESCRIPTION (provided by applicant): Clinical, pathologic and experimental studies support an important role for the macrophages in a broad spectrum of acute (e.g. infections, sepsis) and chronic inflammatory conditions (e.g. obesity and insulin resistance). The initial inflammatory response is orchestrated by macrophages activated by pro-inflammatory stimuli (classically activated M1 macrophages). In contrast, the resolution phase of the inflammatory process is conducted by alternatively activated M2 macrophages. The perturbation in balance between the classically activated M1-type and alternatively activated M2-type macrophages can contribute to various human diseases and inflammatory disorders. Therefore a better understanding of this phenomenon is of considerable scientific and therapeutic interest. Kruppel-like factors are a subclass of the zinc-finger family of transcription factors that regulate key cellular processes such as development, differentiation, proliferation and programmed cell death. However, the role of KLF6 in myeloid cell biology is completely unknown. Our studies to date indicate that, (a) KLF6 expression is elevated in myeloid cells derived from human septic patients; (b) gain and loss-of-function studies revealed that KLF6 promote macrophage M1 polarization while suppressing M2 polarization; (c) Myeloid deficiency of KLF6 enhanced host mortality following infection; (d) Deficiency of myeloid KLF6 attenuated high fat diet induced obesity and glucose intolerance. To better understand the precise role of KLF6 in macrophage polarization and function, following three aims are proposed. In Aim 1, we will investigate KLF6 contribution to pro-inflammatory (M1) macrophage polarization and functions. In Aim 2, we will evaluate KLF6's ability to suppress anti-inflammatory (M2) macrophage polarization and functions. In Aim 3, we will elucidate the role of myeloid KLF6 in development of obesity and metabolic syndrome. Collectively, these studies will define the molecular basis for KLF6-mediated macrophage cell polarization and the functional consequences in inflammatory disease and disorders. The results of these studies will provide the foundation for novel therapies directed at the treatment of a broad spectrum of human chronic and acute inflammatory disease conditions.

描述（由申请人提供）：临床，病理和实验研究支持巨噬细胞在各种急性（例如感染，败血症）和慢性炎症条件（例如肥胖症和胰岛素抵抗）中的重要作用。最初的炎症反应是由促炎性刺激激活（经典激活的M1巨噬细胞）激活的巨噬细胞的。相反，炎症过程的分辨阶段是通过激活的M2巨噬细胞进行的。经典活化的M1型和替代激活的M2型巨噬细胞之间的平衡扰动可以有助于各种人类疾病和炎症性疾病。因此，更好地理解这种现象具有相当大的科学和治疗兴趣。类似Kruppel的因子是转录因子的锌指家族的一个子类，这些因子调节了关键细胞过程，例如发育，分化，增殖和程序性细胞死亡。但是，KLF6在髓样细胞生物学中的作用是完全未知的。迄今为止，我们的研究表明，（a）来自人类化粪池患者的髓样细胞中KLF6表达升高； （b）功能丧失研究表明，KLF6在抑制M2极化的同时促进巨噬细胞M1极化； （c）感染后KLF6的髓样缺乏增强的宿主死亡率； （d）髓样KLF6缺乏减弱高脂饮食诱导的肥胖和葡萄糖不耐症。为了更好地理解KLF6在巨噬细胞极化和功能中的精确作用，提出了三个目标。在AIM 1中，我们将研究KLF6对促炎（M1）巨噬细胞极化和功能的贡献。在AIM 2中，我们将评估KLF6抑制抗炎（M2）巨噬细胞极化和功能的能力。在AIM 3中，我们将阐明髓样KLF6在肥胖和代谢综合征发展中的作用。总的来说，这些研究将定义KLF6介导的巨噬细胞极化以及炎症性疾病和疾病的功能后果的分子基础。这些研究的结果将为旨在治疗广泛的人类慢性和急性炎性疾病疾病的新型疗法提供基础。