Tumor Necrosis Superfamily Ligands and Lymphocytes Role in Liver Regeneration

肿瘤坏死超家族配体和淋巴细胞在肝脏再生中的作用

• 批准号: 8055017
• 负责人: ROBERT A. ANDERS
• 金额: $ 33.25万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-05 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055017
• 关键词: Abbreviations; Address; Alanine Transaminase; American; Antibodies; Apoptosis; Biological Assay; Bone Marrow; Bromodeoxyuridine; Cause of Death; Cell Death; Cell Survival; Cells; Cessation of life; Chimeric Proteins; Chronic Hepatitis; Complex; Culture Media; Cyclin D1; Cyclin E; DNA biosynthesis; Data; Disease; Event; Exhibits; Family member; Fibroblasts; Genetic; Glycoproteins; Goals; Hepatic; Hepatocyte; Herpesviridae; Hour; IL6 gene; Immune; In Vitro; Injury; Interleukin-6; Intravenous; Kinetics; Knock-out; Laboratories; Lead; Ligands; Light; Link; Lipopolysaccharides; Liver; Liver Regeneration; Liver diseases; Lymphocyte; MAP Kinase Gene; Malignant neoplasm of liver; Mediating; Mediator of activation protein; Medical; Membrane; Modeling; Molecular; Monitor; Mus; N-terminal; NF-kappa B; Natural regeneration; Necrosis; Partial Hepatectomy; Pathway interactions; Phosphorylation; Phosphotransferases; Population; Production; Proteins; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; STAT3 gene; Serum; Signal Pathway; Signal Transduction; Small Interfering RNA; Source; System; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Tumor Necrosis Factor-Beta; Tumor Necrosis Factor-alpha; United States; Viral; Viral hepatitis; cell type; cytokine; extracellular; feeding; high voltage electron microscopy; improved; in vitro testing; in vivo Model; intrahepatic; lymphotoxin beta; lymphotoxin beta receptor; member; mortality; prevent; programs; public health relevance; receptor; regenerative; response; stress-activated protein kinase 1; trafficking; tumor

DESCRIPTION (provided by applicant): A remarkable feature of the vertebrate liver is its ability to regenerate following injury. Multiple parallel pathways feed into the regenerative response. We believe that unlocking the systems that control the regenerative response will lead to treatments for liver diseases. We are focusing upon the tumor necrosis factor (TNF) superfamily which is a large group of ligands and receptors with diverse biologic activities. Our laboratory is uncovering the exact intra- and extrahepatocellular events of the TNF related member, lymphotoxin. Specifically, we are examining the mechanisms by which this potent molecule contributes to liver regeneration. We are focusing upon the interactions between the lymphotoxin receptor on hepatocytes and lymphotoxin expressed on immune cells. First, we aim to show what cell survival mechanisms the lymphotoxin beta receptor triggers. Second, we link the production of interleukin 6 and stimulation of STAT3 phosphorylation to the lymphotoxin receptor. Third, we specifically tie the lymphotoxin receptor to the production of IL-6 and the intrahepatic cellular response. Together these aims will define the role of TNF superfamily member in liver regeneration and lead to a better understanding of what causes and could potentially prevent liver injury. PUBLIC HEALTH RELEVANCE: Liver diseases are among the leading causes of death for Americans and few treatments options exist. Our laboratory seeks to understand how the liver responds to injuries. What we discover is relevant to livers diseases such as viral and non-viral hepatitis, chronic liver disease and liver cancer.

描述(申请人提供)：脊椎动物肝脏的一个显著特征是其在受伤后再生的能力。多条平行的通路进入再生反应。我们相信，解锁控制再生反应的系统将导致肝病的治疗。我们关注的是肿瘤坏死因子超家族，它是一大类具有不同生物活性的配体和受体。我们的实验室正在发现肿瘤坏死因子相关成员淋巴毒素的确切肝内和肝外事件。具体地说，我们正在研究这种强大的分子促进肝脏再生的机制。我们关注的是肝细胞上淋巴毒素受体和免疫细胞上表达的淋巴毒素之间的相互作用。首先，我们的目标是展示淋巴毒素β受体触发的细胞生存机制。其次，我们将白介素6的产生和STAT3磷酸化的刺激与淋巴毒素受体联系起来。第三，我们专门将淋巴毒素受体与IL-6的产生和肝内细胞反应联系起来。这些目标将确定肿瘤坏死因子超家族成员在肝脏再生中的作用，并导致更好地理解是什么导致并可能预防肝损伤。 与公共卫生相关：肝病是美国人的主要死亡原因之一，几乎没有治疗选择。我们的实验室试图了解肝脏对损伤的反应。我们的发现与病毒性和非病毒性肝炎、慢性肝病和肝癌等肝脏疾病有关。