Dendritic Cell Activation by Mitochondrial Transcription Factor A

线粒体转录因子 A 激活树突状细胞

基本信息

批准号：
7707655
负责人：
ELLIOTT D CROUSER
金额：
$ 18.75万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-22 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7707655
关键词：
1-Phosphatidylinositol 3-Kinase Active Sites Acute Acute Disease Animals Antibodies Antigens Apoptosis Area Autoantigens Binding Biological Blocking Antibodies Boxing Burn Trauma Burn injury Cell Death Cells Cellular Structures Complication Coupled CpG dinucleotide Critical Illness DNA DNA Binding DNA-dependent protein kinase Data Dendritic Cells Dendritic cell activation Exploratory/Developmental Grant HMGB1 Protein Human Immune Immune response Immune system Infection Inflammation Inflammation Mediators Inflammatory Interferon Type I Interferons Investigation Laboratories Life Link Mammals Mediating Mediator of activation protein Mitochondria Mitochondrial DNA Mitochondrial Proteins Mus Necrosis Nuclear Organ Pancreatitis Pathway interactions Patients Play Protein Isoforms Proteins Publishing Recombinants Research Role Sepsis Signal Pathway Signal Transduction Small Interfering RNA Sterility Structure TLR9 gene Techniques Testing Tissues Transgenic Mice Trauma United States National Institutes of Health antigen processing arginyllysine cell injury cell type design formyl peptide in vivo inhibitor/antagonist lysylproline monocyte mtTF1 transcription factor protein aminoacid sequence public health relevance receptor receptor for advanced glycation endproducts research study response uptake

项目摘要

DESCRIPTION (provided by applicant): The innate immune system is designed to guard against potentially dangerous infections, but recent studies also show that our immune system can become activated by "self-antigens" which are released during severe acute illnesses, such as trauma, pancreatitis or burns. Under these conditions, tissue damage results in widespread activation of the immune system in the absence of any identifiable infection (i.e., sterile inflammation), which is associated with a dramatic worsening of the patient's condition. Dendritic cells (DCs) are among the immune cells that first respond to antigens released from damaged cells, and new data from our laboratory indicates that mitochondrial components of the cell most vigorously activate DCs. In particular, unmethylated (CpG) mitochondrial DNA when combined with its usual binding partner, mitochondrial transcription factor A (TFAM), is shown to potently activate DCs. We hypothesize that the mitochondrial antigens TFAM and CpG DNA play a major role in the induction of DC activation in the context of acute cell damage. To test this hypothesis three major research aims are proposed: 1) We will determine if RAGE and TLR-9/MyD88 pathways independently contribute to DC activation by TFAM and CpG DNA, 2) we will determine the role of PI-3K/Akt signaling in promoting DC Type 1 interferon responses to TFAM and CpG DNA, 3) we will determine if the DNA-binding Pro-Lys-Arg sequence of TFAM protein is responsible for its pro- inflammatory biological activity. For these studies we will use human DCs and DCs obtained from genetically altered mice lacking RAGE, TLR-9, and MyD88. We will also determine if TFAM and CpG DNA are responsible for the activation of the immune response in mice. These experiments will investigate an antibody directed against TFAM, which may serve as a mechanism to block the activation of the immune system in response to acute cell death, which would have important applications for the treatment of critically ill animals and humans. PUBLIC HEALTH RELEVANCE: This project will determine the mechanisms linking cell and tissue damage to activation of the immune system, which is a common and potentially life-threatening complication in acutely ill patients, such as those suffering from trauma, pancreatitis or burn injuries. Recent studies in our laboratory indicate that dendritic cells, which represent a first line of defense of our immune system, are strongly activated in response to components of mitochondria, which are released from damaged cells. This project will focus on the mechanisms by which a particular mitochondrial protein, mitochondrial transcription factor A (TFAM), engages the immune system to promote inflammation. This project has important implications for understanding how cell and tissue damage, such as commonly occurs in many acute illnesses, can induce activation of the immune system, which is potentially harmful to the host.

描述（由申请人提供）：先天免疫系统旨在防范潜在危险的感染，但最近的研究还表明，我们的免疫系统可以被“自身抗原”激活，这些“自身抗原”在严重的急性疾病期间释放，例如创伤、胰腺炎或烧伤。在这些情况下，在没有任何可识别感染（即无菌性炎症）的情况下，组织损伤会导致免疫系统广泛激活，这与患者病情的急剧恶化有关。树突状细胞 (DC) 是首先对受损细胞释放的抗原做出反应的免疫细胞之一，我们实验室的新数据表明，细胞的线粒体成分最能有效地激活 DC。特别是，当未甲基化 (CpG) 线粒体 DNA 与其通常的结合伴侣线粒体转录因子 A (TFAM) 结合时，可有效激活 DC。我们假设线粒体抗原 TFAM 和 CpG DNA 在急性细胞损伤情况下诱导 DC 激活中发挥重要作用。为了检验这一假设，提出了三个主要研究目标：1) 我们将确定 RAGE 和 TLR-9/MyD88 通路是否独立地促进 TFAM 和 CpG DNA 激活 DC，2) 我们将确定 PI-3K/Akt 信号传导的作用在促进 DC 1 型干扰素对 TFAM 和 CpG DNA 的反应中，3) 我们将确定 TFAM 蛋白的 DNA 结合 Pro-Lys-Arg 序列是否负责其 pro-炎症生物活性。在这些研究中，我们将使用人类 DC 和从缺乏 RAGE、TLR-9 和 MyD88 的基因改造小鼠获得的 DC。我们还将确定 TFAM 和 CpG DNA 是否与小鼠免疫反应的激活有关。这些实验将研究针对 TFAM 的抗体，该抗体可能作为一种机制来阻止免疫系统响应急性细胞死亡而激活，这对于治疗危重动物和人类具有重要的应用。公共健康相关性：该项目将确定细胞和组织损伤与免疫系统激活之间的联系机制，免疫系统激活是急症患者（例如遭受外伤、胰腺炎或烧伤的患者）常见且可能危及生命的并发症。我们实验室最近的研究表明，树突状细胞代表了我们免疫系统的第一道防线，它对受损细胞释放的线粒体成分做出反应，被强烈激活。该项目将重点研究特定线粒体蛋白线粒体转录因子 A (TFAM) 与免疫系统促进炎症的机制。该项目对于了解细胞和组织损伤（例如在许多急性疾病中常见的损伤）如何诱导免疫系统的激活（这对宿主可能有害）具有重要意义。