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Work Address:
710 Westwood Plaza
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Phone Numbers:
310-206-0550
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Recovery after stroke is limited, making it the leading cause of adult disability. The mechanisms of recovery after stroke have remained poorly defined. We have shown that after ischemic injury the adult brain can sprout a limited set of new connections within partially damaged areas, in a process that correlates in magnitude and location with recovery. This axonal sprouting after stroke may be limited by the failure of adult neurons to fully activate a growth program and by the inhibitory cellular environment of the adult brain. Stroke also activates a neuronal growth program in a limited number of stem cells, or neuronal precursors, that proliferate and differentiate into neurons at sites adjacent to the infarct. The long-term objective of this research is to define the molecular mechanisms of a neuronal growth program in the adult brain so as to identify pharmacological targets to improve functional recovery after stroke. The specific goals of the lab are to characterize the growth-promoting and growth-inhibiting genes in the axonal sprouting and neuronal precursor cell responses after stroke.
To accomplish these goals we have developed a model of stroke within the rodent barrel field. This cortical area has a well-characterized anatomy and stereotyped cellular architecture that allow its use as a template to map gene expression within injured and sprouting neuronal circuits and newly differentiating neuronal precursor cells. We are pursuing five lines of investigation with this model. First, we are mapping the expression patterns of a recently described set of regeneration-associated genes during axonal sprouting and neuronal precursor differentiation. Second, we are characterizing the expression pattern of glial-derived molecules that form barriers to axonal sprouting and neuronal precursor migration after stroke. Third, we are studying the functional effects of growth-promoting or growth-inhibitory molecules using selective blocking experiments of individual molecules through antibody or enzyme delivery to the stroke region. Fourth, we are characterizing the signals that lead from localized cell death in the infarct core to the distant stem cell or neuronal precursor response, with a focus on angiogenic signals that may lead to neurogenesis and particular the hypoxia inducible factor/vascular endothelial growth factor/erythropoietin system. Finally, because our data shows that stroke induces neuronal growth programs within specific areas adjacent to the infarct, we have hypothesized that these areas will be instructive for the neuronal differentiation of transplanted stem cells. We are using the maps of growth-associated gene expression derived from the preceding experiments to guide stem cell transplantation after stroke to test this hypothesis.
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