Evaluation of Hypoxia in Grafted Dopamine Neurons

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DESCRIPTION (provided by applicant): Intracerebral neural grafting strategies for neurological disorders are limited by the poor survival rate of grafted cells. For example, the survival rate of dopamine (DA) neurons grafted in parkinsonian animal models and in clinical trials with Parkinson s patients is merely 5-20%. Critical to clinical success is the development of methods whereby grafted DA neuron viability and reinnervation of the host striatum are markedly increased. The focus of this R03 application is to directly examine the role of hypoxia in intracerebral grafts utilizing a well-established paradigm, grafts of mesencephalic DA neurons. Our research indicates that massive apoptosis of grafted mesencephalic cells occurs within the first few days after transplantation and then sharply diminishes. This time course of grafted DA neuron death closely parallels the delay in host vascularization of the grafted cells. The lack of blood-borne oxygen, or hypoxia, experienced by the grafted cells during the immediate post-grafting interval is a likely candidate to trigger apoptotic cell death. However, the role of hypoxia in limiting graft survival has never been directly assessed. The overall hypothesis of this proposal is that grafted DA neuron survival is severely limited by hypoxia during the early post-transplantation interval when grafted cells are not adequately vascularized. Identification of hypoxia as a significant constraint on graft survival would direct future strategies aimed at enhancing intracerebral grafts of numerous cell types (primary cells, stem cells) implanted to treat a wide range of neurological disorders.