Tumor Necrosis Superfamily Ligands and Lymphocytes Role in Liver Regeneration

描述（由申请人提供）：脊椎动物肝脏的一个显著特征是其损伤后再生的能力。再生反应有多条平行通路。我们相信，解开控制再生反应的系统将导致肝病的治疗。肿瘤坏死因子（TNF）超家族是一大类具有多种生物活性的配体和受体。我们的实验室正在揭示TNF相关成员淋巴毒素在肝细胞内和肝细胞外的确切事件。具体来说，我们正在研究这种有效分子促进肝脏再生的机制。我们的重点是肝细胞淋巴蛋白受体和免疫细胞淋巴蛋白表达之间的相互作用。首先，我们的目标是显示淋巴毒素受体触发的细胞存活机制。其次，我们将白细胞介素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，我们明确地将淋巴毒素受体与IL-6的产生和肝内细胞反应联系起来。总之，这些目标将确定TNF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。

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.