Nuclear MT1-MMP and Macrophage Immune Function

核MT1-MMP与巨噬细胞免疫功能

基本信息

批准号：
9173451
负责人：
STEPHEN J WEISS
金额：
$ 38.88万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9173451
关键词：
Affect Animal Model Attention Basement membrane Behavior Cell Nucleus Cell physiology Cells Chromatin Remodeling Factor Chronic Complement Connective Tissue DNA Binding Disease Elements Endothelial Cells Enzymes Epithelial Cells Event Extracellular Matrix Family member Gene Family Gene Targeting Genes Genetic Transcription Host Defense Human Immune Immune Response Genes Immune response In Vitro Inflammation Inflammatory Inflammatory Response Interleukin-10 Interleukin-6 Length MMP14 gene Matrix Metalloproteinases Mediating Mediator of activation protein Membrane Molecular Morbidity - disease rate Mus Myeloid Cells NURF NuRD complex Nuclear Nucleoplasm Outcome Pathway interactions Peptide Hydrolases Play Population Process Reporting Research Design Role Series Signal Transduction Site System TLR4 gene TNF gene Therapeutic Intervention Tissues Trans-Activators Transactivation Transcriptional Activation chemokine cytokine immune function immunoregulation in vitro activity in vivo insight interstitial macrophage membrane-type matrix metalloproteinase mortality novel programs promoter public health relevance response trafficking

项目摘要

DESCRIPTION (provided by applicant): During events ranging from host defense to chronic inflammatory disease states, macrophages (MOs) infiltrate affected interstitial tissues where they can participate in both the proteolytic remodeling of the extracellular matrix and local immune responses. MOs have long been assumed to mobilize proteolytic enzymes (particularly those belonging to the matrix metalloproteinase gene family) in order to remodel the extracellular matrix. However, increasing evidence suggests that MMPs can also regulate cell function independently of their matrix remodeling activities. In an attempt to characterize matrix metalloproteinase-dependent versus -independent functions in MOs, we have recently focused our attention on the membrane-anchored protease, MT1-MMP - the single MMP family member whose deletion in mice results in a profound increase in morbidity and mortality. In recently reported studies designed to compare and contrast the function of wild-type and MT1- MMP-null MOs, we discovered that MO-derived MT1-MMP acts as a previously unsuspected transactivator of the gene networks central to MO inflammatory responses. MT1-MMP exerts these effects on MO function by controlling a novel regulatory axis wherein LPS-TLR4 interactions trigger MT1-MMP expression which then acts as a required activator of PI3K�/Akt/GSK3 signaling and the Mi-2/NuRD complex of nucleosome remodeling factors. Importantly, but unexpectedly, MT1-MMP exerts control over MO immune responses by trafficking into the nuclear compartment where it associates with the PI3K� promoter. While similar - if not identical - processes are operative in human cells, the mechanisms that control MT1-MMP nuclear trafficking and translocation remain undefined as do the processes that control MT1-MMP-DNA binding interactions or target gene selection. Furthermore, independent of MT1-MMP function in the nuclear compartment, the proteinase also serves as a key effector of MO-mediated turnover of the extracellular matrix, particularly those components associated with basement membranes, the specialized connective tissue barriers that underlies all epithelial and endothelial cells. As such, we propose to i) characterize the regulatory mechanisms underlying MT1-MMP nuclear trafficking and nucleoplasm translocation, ii) identify the DNA-binding partners that mediate MT1-MMP-mediated nuclear transcriptional activation iii) define the role of MT1-MMP as the dominant mediator of extracellular matrix remodeling and iv) characterize the role of MO MT1-MMP in regulating immune responses in vivo. These studies should provide novel insights into newly identified, MO- dependent nucleosomal remodeling pathways that mark chronic inflammatory events central to host defense as well as inflammatory disease states. As MT-MMPs and PI3K� are expressed in almost all immune cell populations, these results should serve to outline a new paradigm in inflammation and identification of control mechanisms that may prove conducive to therapeutic intervention.

描述（由申请人证明）：从宿主防御到慢性炎症状态的事件中，它们可以参与细胞外基质的BoteSolotic Regodepers的时间MMP还可以独立于其矩阵重塑活性，以表征矩阵金属酶依赖性酶 - 依赖于ASH，我们最近将其集中在最近报道的研究和对比的研究中。 MT1-MMP-NULL MOS，我们发现MO衍生的MT1-MMP充当Mo炎症反应中心的基因网络的iivator MMP的表达是Actired Activor的3K活性因子。 f在人类细胞中不相同的过程，控制MT1 -MMP核运输和易位的机制与控制MT1 -MMP -DNA结合相互作用或靶基因选择的过程也不确定。 SERSO是介导的细胞外基质周转率的AKey效应子，特别是地下室的内基梅巴群岛卵形细胞。 MT1-MMP介导的核转录激活iii）将MT1-MMP的作用定义为Trix重塑和IV），表征MT MT1-MMP在调节体内的免疫反应中的作用。 - 在几乎所有免疫细胞种群中表达了宿主防御和炎症疾病状态中心的慢性炎症事件的依赖性核小体重塑途径。可能证明是治疗干预的控制机制。