Innovative Genetic Approaches for Hepatic Repopulation

 描述（由申请人提供）：更好地理解肝脏对毒性损伤的反应，包括肝细胞增殖、兼性肝干细胞（“卵圆细胞”）的活化和分化，以及不幸的是肝细胞癌风险的增加， 这是开发慢性肝病新型临床治疗和改善癌症预防的先决条件。同样，细胞替代疗法，无论是通过直接肝细胞移植还是在生物人工肝装置中，都需要改进，以便成为肝移植的可靠替代方案。迄今为止，肝细胞增殖的研究经常集中在部分肝切除术范例上，这是一种“非损伤”模型，不能反映人类的肝损伤，因此未能确定用于改善毒性损伤后再生或限制人类HC增殖的特异性靶点。在具体目标1中，我们将使用创新的遗传方法确定哪些基因和基因组合促进或抑制中毒性肝损伤后的肝细胞再生。在特定目标2中，我们将采用关键肝脏转录因子的表达来改善肝祖细胞向功能性肝细胞的分化。总之，这些方法将提供对肝脏对毒性损伤的反应的更好理解，并促进发现新的细胞替代疗法来治疗慢性肝病和肝硬化。 失败

 DESCRIPTION (provided by applicant): A better understanding of the liver's response to toxic injury, which includes hepatocyte proliferation, activation and differentiation of facultative hepaic stem cells ("oval cells"), and - unfortunately - an increased risk for hepatocellular carcinoma, is a prerequisite for the development of novel clinical treatments for chronic liver disease and improved cancer prevention. Likewise, cell replacement therapy, either through direct hepatocyte transplantation or in bio-artificial liver devices, needs to be improved in order to become a reliable alternative to liver transplantation. To date, investigations of hepatocyte proliferation have frequently focused on the partial hepatectomy paradigm, a "noninjury" model that is not reflective of liver injury in humans and which has therefore failed to identify specifi targets for either improved regeneration following toxic injury or for limiting proliferation in HC in humans. In Specific Aim 1, we will determine which genes and gene combinations promote or repress hepatocyte repopulation following toxic liver injury using an innovative genetic approach. In Specific Aim 2, we will employ expression of key hepatic transcription factors to improve the differentiation of hepatic progenitor cells to functional hepatocytes. Together, these approaches will provide an improved understanding of the liver's response to toxic injury, and facilitate the discovery of new cell replacement therapies to treat chronic liver disease and liver failure.