Cerebrovascular accidents of ischemic origin constitute a major cause of persistent neurologic deficits. The development of immediate therapy for brain ischemia has focused on thrombolytic or neuroprotectant mechanisms. A complimentary treatment approach for lessening the stroke-related disability is to promote the rearrangement of axonal connectivity amongst surviving neurons. It is known that the plasticity of adult neuronal connections is quite limited. Previous work has indicated that CNS myelin proteins play a role in limiting the degree of axonal regeneration after traumatic transection in the spinal cord. In particular, the proteins Nogo, MAG and OMgp all bind to a Nogo Receptor (NgR) to inhibit axonal growth. Here, we will examine the relevance of this pathway in recovery from ischemic stroke and we will use this knowledge to develop methods for promoting neurological function after focal brain ischemia. Preliminary data demonstrate that NgR antagonism by genetic or pharmacological means can produce enhanced recovery from stroke. This is separate from neuroprotection. We will extend these studies in . several directions. First, we will consider the therapeutic window for this effect. How long and in what dose is NgR antagonism effective? Are the beneficial effects persistent or reversible and are they age- dependent? We will also explore the mechanism of these effects by characterizing the axonal connectivity of selective fiber systems and cortical maps. Both to develop alternative pharmacologic approaches and to verify the NgR antagonistic mechanism, additional treatments that alter upstream and downstream molecules in the NgR pathway willbe studied. Overall, this work will determine the extent to which enhanced axonal plasticity created by blockade of NgR function improves stroke recovery.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZHL1-CSR-H (O1))
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Bosetti, Francesca
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Yale University
Schools of Medicine
New Haven
United States
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