Toll like receptor - Mediated pathways in liver injury

Toll 样受体 - 肝损伤的介导途径

基本信息

批准号：
8035436
负责人：
Gyongyi Szabo
金额：
$ 33.84万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8035436
关键词：
Agonist Anti-Inflammatory Agents Anti-inflammatory Attenuated Bone Marrow CCL17 gene CCL2 gene CXCL10 gene Cause of Death Cells Chimera organism Clinical DNA Data Development Disease Granuloma Hepatic Granuloma Hepatocyte Immune Immune system Infiltration Inflammation Inflammatory Injury Injury to Liver Interferon Type I Interferons Interleukin-10 Interleukin-12 Interleukin-18 Invaded Life Ligands Liver Liver Failure Liver diseases Macrophage Inflammatory Protein-1 Mediating Molecular Pathway interactions Pattern Play Population Predisposition Primary biliary cirrhosis Process Production Propionibacterium acnes Regulation Role Sarcoidosis Signal Pathway Signal Transduction Specificity TLR2 gene TLR4 gene Testing Therapy Clinical Trials Time Toll-like receptors Vaccines chemokine clinically relevant cytokine design human disease insight novel therapeutic intervention pathogen prevent receptor-mediated signaling research study response

项目摘要

DESCRIPTION (provided by applicant): Liver failure, which can cause death, in most cases is a result of multiple insults. The mechanisms for sensitization to liver injury are not well understood. Pathogen-derived signals recognized by Toll-like receptors can activate both hepatocytes and immune cells in the liver to induced inflammation and sensitization to live injury. Our preliminary data suggest that administration of CpG DNA, a TLR9 ligand, results in granuloma formation and sensitization to a TLR4-lingad-induced liver injury. We postulate that TLR2 activation can amplify TLR9-induced sensitization to subsequent liver injury. We hypothesize that the presence of the common TLR adaptor, MyD88, is critical for granuloma formation and sensitization by TLR9 and TLR2-ligands but also by pathogens such as P. acnes. The Specific Aims of our studies are: 1. To delineate the mechanisms of TLR9-induced granuloma formation and sensitization to subsequent liver injury by a) investigating the role of key cytokines (IFN , IL-12, IL-18) and b) characterizing the inflammatory cell populations involved in granulomas and chemokines (MIP-1?, MCP-1, Mig, IP-10, MDC and TARC ) involved in their recruitment. 2. To investigate the mechanisms of TLR2-mediated amplification of TLR9-induced liver granulomas and sensitization to TLR-induced liver injury by a) testing involvement of adaptor molecules and TLR-mediated downstream signaling in immune cells and in the liver, b) evaluating the role of type I interferons. 3. To determine the role of bone marrow-derived immune cells and liver parenchymal cells in induction of granulomas and sensitization to liver injury and to investigate cross-regulation between these cell populations by testing TLR9-/- or MyD88-/- bone marrow chimeras. Results from these experiments will help to understand molecular pathways that are involved in pathogen-induced sensitization to liver failure. Our results will also help better understand formation of granulomas in the liver that is a common feature of primary biliary cirrhosis and sarcoidosis, diseases with no definitive treatment options at this time. Thus, our study may help to design new therapeutic approaches to prevent liver diseases with granulomas and to attenuate sensitization to liver injury caused by infectious pathogens.

描述（申请人提供）：在大多数情况下，可能导致死亡的肝衰竭是多次侮辱的结果。对肝损伤的敏化机制尚不清楚。通过Toll样受体识别的病原体信号可以激活肝脏中的肝细胞和免疫细胞，从而诱导炎症和敏感性对生命损伤。我们的初步数据表明，CPG DNA（TLR9配体）的给药会导致肉芽肿的形成和敏化对TLR4-LINGAD诱导的肝损伤。我们假设TLR2激活可以扩大TLR9诱导的敏化为随后的肝损伤。我们假设普通TLR衔接子MyD88的存在对于TLR9和TLR2配体的形成和敏化至关重要，也是病原体（例如痤疮疟原虫）的敏化至关重要的。我们的研究的具体目的是：1。描述TLR9诱导的肉芽肿的形成和对随后肝损伤的敏感性的机制，通过a）研究涉及炎症细胞群中的关键细胞因子（IFN，IL-12，IL-10）和iPC和Chanulomas和Chenulomas和Chemokins和MIP-1？MIP-1？，MIP或MIP-1？）参与他们的招聘。 2。研究TLR2介导的TLR9诱导的肝粒瘤的扩增和对TLR诱导的肝损伤的敏化，通过a）测试适应器分子的参与以及TLR介导的Immune细胞中的TLR介导的下游信号传导，b）在肝脏中，b）评估I型i粒子的作用。 3。确定骨髓来源的免疫细胞和肝实质细胞在诱导颗粒瘤和对肝损伤的敏感性方面的作用，并通过测试TLR9 - / - 或MYD88 - / - - / - - 骨髓嵌合体来研究这些细胞种群之间的交叉调节。这些实验的结果将有助于理解与病原体诱导的对肝衰竭敏感的分子途径。我们的结果还将有助于更好地了解肝脏中肉芽肿的形成，这是原发性胆道肝硬化和结节病的常见特征，目前尚无确切治疗方案的疾病。因此，我们的研究可能有助于设计新的治疗方法，以防止患有肉芽肿的肝病，并减轻感染性病原体引起的肝损伤的敏感性。