Mechanisms of In Vivo Cell Fusion

描述（由申请方提供）：通过移植骨髓细胞的细胞融合获得的肝细胞具有增殖能力，并在代谢性肝病动物模型（富马酰乙酰乙酸水解酶（Fah）敲除小鼠）中完全恢复异常肝功能。然而，自发融合是非常罕见的事件，并且仍然远低于治疗效用所需的阈值，除非融合产物具有强的选择性生长优势。此外，融合衍生的肝细胞的基本性质，如基因组稳定性，中心体数量和核重编程的效率是未知的。本申请的总体目标是确定体内细胞融合是否可能是可行的治疗策略。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物的性质。最后，将研究提高体内细胞融合效率的方法。目的1：阐明肝内融合过程的细节。目的2：确定融合肝细胞的相关特性。目的3：通过表达融合性病毒包膜蛋白来增强体内细胞融合。

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.