KLF2 as a novel regular for monocyte activation and function

KLF2 作为单核细胞激活和功能的新型调节剂

• 批准号: 7467751
• 负责人: HIRANMOY DAS
• 金额: $ 12.41万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-17 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7467751
• 关键词: Acute; Andro-Diane; Arthritis; Biological; Biology; Blood; Blood Circulation; CCL2 gene; Cardiovascular system; Carrageenan; Cartilage; Cell Line; Cells; Cellular Immunology; Cellular biology; Characteristics; Chronic; Class; Collaborations; Complex; Condition; Cytokine Activation; Data; Depth; Development; Disease; Doctor of Philosophy; Edema; Experimental Models; Family; Fibroblasts; Gene Expression; Gene Targeting; Generations; Hematopoietic; Human; Immune; Immunodeficient Mouse; Immunohistochemistry; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Invaded; Joints; Knowledge; Kruppel-like transcription factors; Laboratories; Leukocytes; Lipopolysaccharides; Macrophage Activation; Mediating; Mediator of activation protein; Mentors; Modeling; Molecular Biology; Mus; NF-kappa B; PCAF gene; PTGS2 gene; Pathogenesis; Pathway interactions; Phagocytosis; Play; Population; Principal Investigator; Program Development; Protein Overexpression; Range; Regulation; Research; Research Institute; Rheumatoid Arthritis; Role; Signal Transduction; Site; Small Interfering RNA; T-Lymphocyte; Thromboplastin; Tissues; Training; Training Programs; Transcription Coactivator; Transcription Factor AP-1; Transcriptional Regulation; Transgenic Animals; Transgenic Mice; Transgenic Model; Universities; Wound Healing; Zinc Fingers; base; bone; career; cell type; chemokine; cytokine; design; experience; in vivo; in vivo Model; interest; macrophage; member; monocyte; neovascularization; novel; novel strategies; p300/CBP-Associated Factor; peripheral blood; programs; promoter; reconstitution; research study; response; skills; transcription factor

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the development of an academic career in Cardiovascular Transcriptional Biology. The principal investigator has scientific background with expertise in cellular immunology. He will now embark upon a program which is particularly designed to expand his scientific experience, such that he develops the skills required for an independent research career. This program will provide in-depth knowledge and experience in molecular biology, in particular transcriptional regulation, and in transgenic animal studies. Dr. Mukesh K. Jain, MD, will mentor the principal investigator's scientific development. Dr. Jain has a very active laboratory and is the Director of Cardiovascular Research Institute, Case Western Reserve University, Cleveland OH. He has trained several research fellows. The candidate's training will be enhanced by the collaboration with Prof. Diane Mathis, PhD - an expert in the field of arthritis and inflammation research. The project is designed to determine the effect of the transcription factor KLF2 on monocyte activation and function. Preliminary data demonstrate that this factor is expressed in monocytes, and reduced upon cytokine activation or differentiation. Furthermore, forced overexpression of KLF2 in monocytes inhibits the LPS-mediated induction of proinflammatory factors, cytokines and chemokines and reduced phagocytosis. Conversely, short interfering RNA-mediated reduction in KLF2 increased inflammatory gene expression. Mechanistically, KLF2 inhibits the transcriptional activity of both NF-kB and activator protein-1 in part by means of recruitment of transcriptional coactivator p300/CBP-associated factor, PCAF. These observations implicate KLF2 as a novel negative regulator of monocytic activation. The proposed experiments in this application will build on these initial observations and explore them in depth - both mechanistically and in models of arthritis in vivo. Studies will include a detailed analysis of effect on target genes with KLF2 overexpression (by adenoviral overexpression and transgenic models) and siRNA-mediated 'knockdown' approaches. KLF2 transgenic mice will be studied to assess the effects of this factor on the development of arthritis in vivo. Proposal was made to generate acute/ chronic arthritis in KLF2 transgenic mice and will be determined their biological consequences by evaluating arthritis development, macrophage recruitment, immunohistochemistry and gene expression during arthritis development. The monocyte is a key cell type in the regulation of the body's inflammatory response. The applicant's identification of the factor KLF2 as a key regulator of monocyte activation may provide the basis for novel therapies directed at limiting inflammation for a broad spectrum of disease states including arthritis.

描述（由申请人提供）：该提案描述了一项为期5年的培训计划，以开发心血管转录生物学的学术职业。主要研究者具有科学背景，具有细胞免疫学专业知识。现在，他将启动一个计划，该计划旨在扩大他的科学经验，以便他发展独立研究职业所需的技能。该程序将提供深入的分子生物学知识和经验，特别是转录调节和转基因动物研究。医学博士Mukesh K. Jain博士将指导主要研究者的科学发展。 Jain博士拥有一个非常活跃的实验室，是克利夫兰俄亥俄州凯斯西部储备大学心血管研究所的主任。他已经培训了几个研究研究员。与关节炎和炎症研究领域的专家Diane Mathis教授合作将增强候选人的培训。该项目旨在确定转录因子KLF2对单核细胞激活和功能的影响。初步数据表明，该因子在单核细胞中表达，并在细胞因子激活或分化后降低。此外，单核细胞中KLF2的过度表达抑制了LPS介导的促炎因子，细胞因子和趋化因子的诱导，并降低了吞噬作用。相反，简短干扰RNA介导的KLF2降低增加了炎症基因表达。从机械上讲，KLF2抑制了NF-KB和活化剂蛋白-1的转录活性，部分通过募集转录共激活因子p300/CBP相关因子PCAF。这些观察结果暗示KLF2是单核细胞激活的新型负调节剂。本应用程序中提出的实验将基于这些最初的观察结果，并深入探索它们 - 无论是机械上还是体内关节炎模型。研究将包括对具有KLF2过表达的目标基因的影响（通过腺病毒的过表达和转基因模型）和siRNA介导的“敲低”方法的详细分析。将研究KLF2转基因小鼠，以评估该因素对体内关节炎发展的影响。提出了在KLF2转基因小鼠中产生急性/慢性关节炎的建议，并将通过评估关节炎的发育，巨噬细胞募集，免疫组织化学和基因表达来确定其生物学后果。单核细胞是调节人体炎症反应的关键细胞类型。申请人将因子KLF2鉴定为单核细胞激活的关键调节剂，可能为限制包括关节炎在内的广泛疾病状态的新型疗法提供了基础。