Mechanisms of In Vivo Cell Fusion

描述(申请人提供)：在代谢性肝病的动物模型富马酸乙酰乙酸酯水解酶(Fah)基因敲除小鼠中，通过移植的骨髓细胞的细胞融合获得的肝细胞具有增殖和完全恢复异常肝功能的能力。然而，自发融合是一种非常罕见的事件，除非融合产品具有很强的选择性生长优势，否则仍远低于治疗实用所需的阈值。此外，融合来源的肝细胞的基本特性，如基因组稳定性、中心体数量和核重新编程的效率尚不清楚。这项应用的总体目标是确定体内细胞融合是否可能是一种可行的治疗策略。为了实现这一目标，我们将阐明导致肝脏细胞融合的一些基本过程。我们还将描述早期和晚期融合产品的特性。最后，对提高体内细胞融合效率的方法进行了研究。目的1：阐明肝内融合过程的细节。目的2：确定融合来源肝细胞的相关特性。目的3：通过表达融合病毒囊膜蛋白促进体内细胞融合。

DESCRIPTION (provided by applicant): Hepatocytes derived by cell fusion of transplanted bone marrow cells have the capacity to proliferate and completely restore abnormal liver function in an animal model of metabolic liver disease, the fumarylacetoacetate hydrolase (Fah) knockout mouse. However, spontaneous fusion is a very rare event and remains far below the threshold required for therapeutic utility unless the fusion products have a strong selective growth advantage. Furthermore, basic properties of fusion-derived hepatocytes such as genomic stability, centrosome number and efficiency of nuclear reprogramming are unknown. The overall goal of this application is to determine whether in vivo cell fusion could be a viable therapeutic strategy. To achieve this goal we will clarify some of the basic processes that lead to cell fusion in the liver. We will also delineate the properties of early and late fusion products. Finally, methods to enhance the efficiency of cell fusion in vivo will be studied. Aim 1: To elucidate details of the intrahepatic fusion process. Aim 2: To determine relevant properties of fusion-derived hepatocytes. Aim 3: To enhance in vivo cell fusion by expression of fusogenic viral envelope proteins.