KLF4, TGF-b1, and transplantation arteriosclerosis

KLF4、TGF-b1 与移植动脉硬化

• 批准号: 7034845
• 负责人: MARK W FEINBERG
• 金额: $ 42.25万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7034845
• 关键词: RNA interference; arteriosclerosis; binding sites; cell adhesion; cytokine; gel mobility shift assay; gene expression; genetic promoter element; genetically modified animals; heart transplantation; inflammation; laboratory mouse; leukocyte activation /transformation; macrophage; medical complication; nitric oxide synthase; protein protein interaction; protein structure function; transcription factor; transforming growth factors; transplantation immunology; vascular endothelium; yeast two hybrid system

DESCRIPTION (provided by applicant): 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-plays a key role in TAA. Through elaboration of inflammatory cytokines, uptake of oxidized lipids, and release of proteolytic enzymes, 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.

描述（由申请人提供）：移植相关动脉硬化（TAA）是心脏移植后存活超过一年的受者死亡的主要原因。TAA的特征是炎性细胞浸润，随后形成弥漫性同心新生内膜，其中平滑肌细胞和巨噬细胞聚集。免疫系统的细胞，特别是巨噬细胞，在TAA中起着关键作用。活化的巨噬细胞通过产生炎性细胞因子、摄取氧化脂质和释放蛋白水解酶，对TAA至关重要。因此，鉴定调节巨噬细胞活化的因子至关重要。Kruppel样因子家族的成员是在调节细胞分化和活化中起重要作用的转录因子。我们鉴定了该家族的一个成员，称为KLF 4，其表达在体内与心脏移植病变相关的巨噬细胞中高度表达。KLF 4表达与响应于干扰素-γ的活化巨噬细胞的诱导相关，并且响应于抗炎生长因子转化生长因子-β 1（TGF-β 1）而降低。KLF 4在巨噬细胞中的过表达有效地诱导巨噬细胞活化的标志物，如iNOS，并抑制TGF-β 1介导的作用。这些观察结果使我们提出了一个中心假设，即KLF 4是巨噬细胞活化和TAA的关键调节因子。在本提案的AIM 1中，我们探索了KLF 4抑制TGF-β 1信号传导能力的机制基础。在AIM 2中，我们检测了KLF 4诱导巨噬细胞iNOS基因表达的能力。最后，在AIMS中，我们评估了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。这些研究的结果是相当大的科学兴趣，并可能作为新的治疗策略，以调节TAA和巨噬细胞对细胞因子刺激的反应的基础。