KLF4, TGF-b1, and transplantation arteriosclerosis

KLF4、TGF-b1 与移植动脉硬化

• 批准号: 7820830
• 负责人: MARK W FEINBERG
• 金额: $ 3.74万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7820830
• 关键词: Adhesions; Affect; Age; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Arteriosclerosis; Asses; Atherosclerosis; Base Pairing; Binding; Binding Sites; Cause of Death; Cell Differentiation process; Cell Line; Cells; Coronary artery; DNA Binding; Development; Diffuse; Dominant-Negative Mutation; Enzymes; Erythropoiesis; Family; Family member; Gelshift Analysis; Gene Chips; Gene Expression; Genes; Growth Factor; Heart Transplantation; Human; Immune system; Infiltration; Inflammatory; Interferon Type II; Lesion; Macrophage Activation; Mediating; Methods; Molecular; Peptide Hydrolases; Phase; Plasminogen Activator Inhibitor 1; Play; Process; Production; RNA Interference; Research Personnel; Role; Screening procedure; Series; Signal Pathway; Signal Transduction; Site; Smooth Muscle Myocytes; Structure; T-Cell Activation; Tissue Sample; Transforming Growth Factors; Transplantation; Zinc Fingers; base; chemokine; cytokine; in vivo; insight; interest; macrophage; member; novel therapeutics; overexpression; prevent; programs; promoter; research study; response; transcription factor; vascular inflammation; yeast two hybrid system

Transplantation-associated arteriosclerosis (TAA) is the major cause of death in recipients who survive more than one year after cardiac transplantation. TAA is characterized by infiltration of inflammatory cells followed by the formation of a diffuse, concentric neointima in which smooth muscle cells and macrophages accumulate. Cells of the immune system-particularly the macrophage-play a key role in TAA. Through elaboration of inflammatory cytokines/ growth factors and release of proteolytic enzymes and chemokines, activated macrophages are critical to TAA. As such, identification of factors that regulate macrophage activation is of critical importance. Members of the Kruppel-like family of factors are transcription factors which play important roles in regulating cell differentiation and activation. We identified a member of this family termed KLF4 whose expression is highly expressed in macrophages associated with heart transplant lesions in vivo. KLF4 expression correlates with the induction of activated macrophages in response to interferon-gamma and is decreased in response to the anti-inflammatory growth factor, transforming growth factor-betal (TGF-b1). KLF4 overexpression in macrophages potently induces markers of macrophage activation such as iNOS and inhibits effects mediated by TGF-b1. These observations have led us to the central hypothesis that KLF4 serves as a critical regulator of macrophage activation and TAA. In AIM1 of this proposal we explore the mechanistic basis for KLF4's ability to inhibit TGF-b1 signaling. In AIM2, we examine the ability of KLF4 to induce macrophage iNOS gene expression. Finally, in AIMS, we assess the consequences of KLF4 overexpression on the development of TAA and on macrophage effector functions. These studies will provide important insight regarding the role of KLF4 in regulating macrophage activation. The results of these studies are of considerable scientific interest and may serve as the basis for novel therapeutic strategies to modulate TAA and the macrophage response to cytokine stimulation.

移植相关动脉硬化（TAA）是受者死亡的主要原因， 心脏移植后一年。TAA的特征是炎性细胞浸润， 通过形成弥漫性、同心的新生内膜，其中平滑肌细胞和巨噬细胞 积累。免疫系统的细胞，特别是巨噬细胞，在TAA中起关键作用。通过 炎性细胞因子/生长因子的加工和蛋白水解酶和趋化因子的释放， 活化的巨噬细胞对TAA至关重要。因此，识别调节巨噬细胞的因素 激活是至关重要的。Kruppel样因子家族的成员是转录因子 其在调节细胞分化和活化中起重要作用。我们确认了一名 KLF 4家族，在心脏移植相关巨噬细胞中高度表达 体内病变。KLF 4表达与诱导活化的巨噬细胞应答 干扰素-γ，并减少响应抗炎生长因子，转化生长 因子β 1（TGF-β 1）。KLF 4在巨噬细胞中的过表达有效地诱导巨噬细胞标志物 激活如iNOS，并抑制TGF-β 1介导的作用。这些观察使我们得出 中心假设KLF 4作为巨噬细胞活化和TAA的关键调节剂。在AIM 1中 我们的建议是探索KLF 4抑制TGF-β 1信号传导的机制基础。在AIM 2中，我们 检测KLF 4诱导巨噬细胞iNOS基因表达的能力。最后，在AIMS中，我们评估 KLF 4过表达对TAA发展和巨噬细胞效应功能的影响。 这些研究将为KLF 4在调节巨噬细胞活化中的作用提供重要的见解。 这些研究的结果具有相当大的科学意义，可以作为新的基础。 调节TAA和巨噬细胞对细胞因子刺激的反应的治疗策略。