This project is based on the rationales that neuron degeneratiDn and death, irrespective of the initiating causes, require transcriptic nal induction of death-associated genes and that such genes and the pathways that are up- and down-stre>am of them are therefore potential ta rgets for therapeutic intervention in Parkinson's Disease (PD). There are four interlinked steps in our prograrn. The first was a '"discovery" step that used "SAGE: analysis to identify pro-apoptotic genes induced in a cellular model of PD. Among the induced genes was one designated RTP801and this was found to be both sufficient and necessary for death in our cellular PD models. The set;ond step was "verification" of relevanee to PD and demonstrated that RTP801 is elevated in dopaminergic neurons of PD patients. The third step involved studying the "mechanisms" by which RTP801 is regulated and by which it mediates neijron degeneration and death. This revealed that RTP801 acts in part b;/ suppressing activation of the cellular kinase mTor and that it promotes neuron death by leading to inactivation of the neuronal survival-prc moting kinase AKT. Moreover, mechanism studies with the mTor inhibitor rapamycin show that mTor also acts upstream of RTP801 and is required for its induction, both in cuIture and in an animal model. The Ialter findings led us to preliminary incursions into the fourth step of the program, "therapeutics". Raparnycin, which suppresses RTP801 induction, protects neuronal cells from PDmimetics inculture and inanainimal model. In aggregate, these findings advanced our long-term goal of developing a therapeutic strategy for suppressing neuron degeneration and death in PD and form the basis for the following spejcific aims:
Aim 1 : To define the pathways that govern RTP801 indueDtion and by which it triggers degenei?ation and death a. To test in PD the "AKT hypothesis" that elevated Fn"P801 promotes neuron degeneration and death by depleting activated AKT b. To identify the apoptotic signaling pathways that are activated downstream of RTP801 induction and AKT depletion and that mediate neuron death in PD models and in PD c. To identify the upstream transcription factors that induce RTF3801 in PD models and in PD.
Aim 2 : To further explore (in culture and animal models) the role of mTor signaling in RTP801 induction and to further evaluate the potential of mTor inhibition as a therapeutic for PD.
Aim 3 : To examine the role of RTP801 in neuron degeneration and death in a genetic model of PD.
Aim 4 : To test the hypothesis that the gene Trb3 that is induced in our cellular model of PD contributes to neuron death by acting along with RTP801 to s uppress AKT activation.
(Seeinstructions): Parkinson's disease is a progressive and debilitating neurodegenerative disorder. The ultimate goal of these studies is to identify therapeutic targets for treatment of PD and to point the way o drugs that can be developed towards this end. Our program has thus far found several potential targets in this regard as well as a drug for potential therapeutic development. The proposed work will continue to exploit these findings.
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