The retrovirus ts1, a temperature-sensitive mutant of Moloney murine leukemia retrovirus, resembles human HIV-1 and induces neurodegeneration in FVB/N mice. Using the ts1-infected animal model, we have identified that oxidative stress is a major mechanism in the pathogenesis of ts1 induced neurodegeneration. Our recent results show that ATM, P53, MAPK and mTOR are critically involved in ts1-induced neurodegeneration. Our overall objective is to understand how ts1 induces ROS and whether antioxidants such as GVT, NAC amide prevent ROS-related neurodegeneration in the animal model.

   

      

ATM is a multifunctional protein kinase that regulates cell cycling and cellular responses to events that damage DNA. In ATM knockout (Atm-/-) mice and A-T humans, fatal thymic lymphomas commonly develop early in life, but the mechanisms leading to this symptom remain unclear. Our first study with this model disclosed that the spontaneous DNA synthesis is markedly increased in Atm-/- thymocytes. In later work, we learnt that the increased DNA synthesis represents a failure of T cell development in Atm deficiency, which eventually produce thymic atrophy (immunodeficiency), apoptosis, and tumorigenesis. Recently, we showed that oncoprotein c-Myc levels are progressively increased in Atm-/- thymocytes, and that deregulation of mTOR signaling in these cells is an initial factor to drive c-Myc overexpression and eventually tumors. We are now focusing on the network among ATM, ROS, PTEN, AKT, mTOR in thymocyte development and lymphoid tumorigenesis.