Grants and Contracts Details
Description
Although some of the cellular mechanisms of stroke development are fairly well understood, the neuronal death after ischemic stroke cannot be well controlled because of a lack of efficient treatments. The long-term goal of my research is to develop an effective strategy for ischemic stroke therapy. In the searching for new approaches for stroke therapy, I focus on targeting the post-ischemic inflammation at blood-brain barrier (BBB), because post-ischemic inflammation at the level of brain endothelium of the BBB plays an important role in pathology of ischemic stroke. We propose a novel solution in the proposal which is replacing the anti-ICAM-1 antibody with a RNA nanoparticle (named FRS-NP) consisting of anti-ICAM-1siRNA, packaging RNA (pRNA) of bacteriophage phi29, and a transferrin receptor (TfR) specific RNA aptamer (FB4). The pRNA is used as a vector to carry anti-ICAM-1 siRNA and FB4. The ligand targeting transport function and inhibitory function in ICAM-1 expression of FRS-NP are carried by FB4 and anti-iCAM-1siRNA, respectively. We will use the transient middle cerebral artery occlusion ischemic stroke model (tMCAO) as the brain ischemia/reperfusion (IR) injury model in vivo to demonstrate the feasibility of this vascular targeting strategy for treatment of ischemic stroke. The objective of this application is to develop a BBB targeted RNA complexes for therapy of ischemic stroke. Our central hypothesis is that the FRS-NPs have therapeutic effects on ischemic stroke by inhibition of post-ischemic inflammation. The expected outcomes of the proposed project are that FRS-NPs can be delivered into the brain endothelial cells at the BBB and exert an anti-inflammatory effect by inhibition of ICAM-1 expression, which leads to improvement of ischemic stroke outcomes. Targeting post-ischemic inflammation will give relatively longer therapeutic window, which is highly relevant to clinical application. If successful, it will explore a new therapeutic strategy for ischemic stroke, and this approach could be broadly applied for therapy of diseases affecting the BBB and the central nervous system (CNS).
Status | Finished |
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Effective start/end date | 6/1/15 → 1/16/16 |
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