Aging is associated with a striking increase in the incidence of stroke and neurodegenerative diseases, which are major causes of disability among those aged 70 years and older in the United States. Despite progress in understanding molecular mechanisms of neuronal cell death in these diseases, widely effective treatment remains elusive. Exciting new prospects for human stem cell therapy have been raised by the observation that neurogenesis continues to occur throughout life in the rostral subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus in the adult brain, including aged brain. However, whether the capacity for neurogenesis and the fate of newborn neural cells remain the same or change in aged brain, and whether the neurons produced actually contribute to functional recovery of the aged brain after cerebral injury are unclear. Clarification of these issues will give us a better understanding of the biology of endogenous stem/progenitor cells in aged brain and more insight into the potential of cell therapy for age-related diseases such as ischemic stroke and neurodegenerative disorders. ? ? The following specific aims will be addressed: ? ? 1. Explore whether endogenous neurogenesis is increased, decreased or unchanged in aged compared to young adult and middle-aged rats after focal cerebral ischemia and determine the regional and temporal profiles of neurogenesis after focal cerebral ischemia in vivo. ? ? 2. Determine the destinations of newly generated neural stem/progenitor cells from SVZ and SGZ of the hippocampal dentate gyrus in young adult, middle-aged and aged rat brain after ischemia. ? ? 3. Establish whether administration of the same or different neurogenesis factors promotes neurogenesis in aged compared to young adult and middle-aged rat brain and improves functional outcome after focal cerebral ischemia in vivo. ? ? 4. Determine whether neuronal cells that migrate from SVZ and SGZ develop mature phenotypic neuronal features and exhibit functional properties of neurons in young adult, middle-aged and aged rat brain after focal cerebral ischemia in vivo. ? ?
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