1. The role of foxa2 in the survival of dopamine neurons. ? ? Animals that have only one copy of the foxa2 gene show spontaneous loss of dopamine neurons with age. This mouse will likely be very widely used because although many mutations have been identified that contribute to Parkinsons disease and related disorders, it has been difficult to reproduce the specific loss of dopamine neurons in an animal model. This animal has the potential to teach us a number of important lessons: why some dopamine neurons are more at risk than others, why the disease is progressive and why dopamine neurons are sensitive to mutations in genes that are widely expressed? ? ? Much of what is known about the relationship between the various symptoms in Parkinsons patients and the underlying defects in the nigrostriatal system comes from lesion studies in the rat. The foxa2 heterozygous mouse allows us to study for the first time, in an animal model, motor and cognitive behaviors in the context of a progressive neurodegenerative process. We are currently focused on the cellular role of foxa2 in dopamine neurons. In brain slices, we have shown that the cellular location of the foxa2 gene is controlled by inputs that signal health or stress. This result provides a way measuring the signaling logic that controls the survival of dopamine neurons. ? ? 2. Supporting dopamine neuron survival in vivo.? ? We have shown that a single intra-ventricular injection of Notch ligands alone or in combination with other angiogenic factors promotes widespread activation of the stem cell niche in the adult brain and rescues dopaminergic neurons in a model of PD. These data suggest vascular cytokines promote regenerative responses to brain injury. A major goal of our group is to set up in vitro assays that predict the activation of the stem cell compartment in vivo. In this project, we will use our growing understanding of survival signaling in the stem cell niche to rescue injured dopamine neurons in vivo. This approach may allow a more rapid transition to clinical application than cell replacement therapy. In the past year, we have shown that the major regenerative features found in the adult rat brain are also present in adult monkeys. This result encourages our continued belief in the clinical potential of this approach.
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