KLF2 Mediated HIF-1 Regulation and Macrophage Activation

KLF2 介导的 HIF-1 调节和巨噬细胞激活

• 批准号: 7713630
• 负责人: Ganapati Holanagadde Mahabaleshwar
• 金额: $ 9万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7713630
• 关键词: Affect; Award; Biology; Cell Line; Cells; Cellular biology; Development; Development Plans; Disease; Enzymes; Exhibits; Faculty; Family; Foundations; Funding; Gene Expression; Goals; HIF1A gene; Hypoxia; Hypoxia Inducible Factor; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Laboratories; Lipopolysaccharides; Macrophage Activation; Matrix Metalloproteinases; Mediating; Mentorship; Metabolism; Modeling; Molecular; Molecular Genetics; Mus; Myelogenous; Pathologic; Performance; Physiological; Play; Principal Investigator; Process; Production; Proteins; Regulation; Regulatory Pathway; Research; Research Personnel; Resolution; Role; Secondary to; Sepsis; Stimulus; Structure; Testing; Tissues; Training; Translating; Zinc Fingers; base; career; career development; cell motility; cellular development; chemokine; cytokine; design; experience; gain of function; in vivo; interest; loss of function; macrophage; member; migration; monocyte; novel; response; transcription factor; tumor

DESCRIPTION (provided by applicant): The inflammatory response is critical in regulating a broad spectrum of physiologic and pathologic states. The tissue macrophage is a central regulator of this response - from initiation to resolution o inflammation. Recent studies have identified Hypoxia-inducible Factor 1alpha(HIF-1 alpha) as a key regulator of macrophage activation function. Using a combination of gain- and loss-of-function approaches, the PI has identified KLF2 as a novel endogenous regulator of HIF-1 alpha expression and function. Specifically, our studies show that (1) KLF2 inhibits HIF-1 expression and transcriptional activity; (2) altering KLF2 expression affects HIF-lalpha target gene expression, ATP production, cytokine/MMP expression, and bacterial/tumoricidal activity of macrophages. In this proposal a combination of molecular and genetic approaches will be undertaken (1) to determine the molecular basis for KLF2-mediated inhibition of HIFlalpha expression, (2) to evaluate the effect of altering KLF2 levels on hypoxia or LPS mediated activation of macrophages, and (3) to assess the effect of altering KLF2 levels on hypoxia or LPS-mediated macrophage function in vivo. These studies will provide the foundation for the applicant to achieve his long-term goals of translating basic mechanisms of inflammation toward the development of novel therapies. Support of this project via a K99/R00 award would play a pivotal and requisite role in the candidate's development into an independent investigator. His immediate goal is to solidify his research experience through additional intensive mentorship, technical training, and broad intellectual development that will result directly from this proposal. A highly structured career development plan is an intrinsic component of this proposal and is designed to greatly enhance accomplishment of the candidate's long-term career goal: independent performance of immune cell biology research as an NIH-funded faculty member.

描述（由申请人提供）：炎症反应对于调节广泛的生理和病理状态至关重要。组织巨噬细胞是该反应的中心调节因子 - 从启动到分辨率O炎症。最近的研究已经确定缺氧诱导因子1alpha（HIF-1α）是巨噬细胞激活函数的关键调节剂。使用增益和功能丧失方法的结合，PI已将KLF2鉴定为HIF-1α表达和功能的新型内源性调节剂。具体而言，我们的研究表明（1）KLF2抑制HIF-1的表达和转录活性。 （2）改变KLF2表达会影响巨噬细胞的HIF-LALPHA靶基因表达，ATP产生，细胞因子/MMP表达和细菌/肿瘤活性。在该建议中，将进行分子和遗传方法的组合（1），以确定KLF2介导的Hiflalpha表达抑制的分子基础（2），以评估KLF2水平改变klf2水平对低氧或LPS介导的巨噬细胞激活的影响，以评估巨噬细胞的激活，并评估（3）的效果（3），（3）的效果（3）降低了KLF2级别的效果。体内。这些研究将为申请人实现其长期目标的基础，以将炎症的基本机制转化为新疗法的发展。通过K99/R00奖对该项目的支持将在候选人发展成为独立调查员的发展中起着关键而必要的作用。他的近期目标是通过额外的强化指导，技术培训和广泛的知识发展来巩固他的研究经验，这将直接由这项提案产生。一项高度结构化的职业发展计划是该提案的内在组成部分，旨在极大地增强候选人的长期职业目标：免疫细胞生物学研究作为NIH资助的教职员工的独立表现。