Mechanisms of Improving Collateral Blood Flow During Ischemic Stroke
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Publisher:The Ohio State University
Series/Report no.:The Ohio State University. Department of Evolution, Ecology, and Organismal Biology Honors Theses; 2014
More than 795,000 Americans suffer a stroke annually, and it is the third leading cause of death in the United States1. There are two types of stroke, hemorrhagic and ischemic. Hemorrhagic stroke is caused by the rupture of blood vessels within the brain, as opposed to ischemic strokes, which are caused by a blockage within the vessel. Of all strokes presented clinically, 86% are ischemic by nature1. Currently, there are few treatments for ischemic stroke. The prevailing early treatments include thrombolytic therapy and antiplatelet therapy such as low dose aspirin2,3. These treatments are each flawed. Tissue plasminogen activator (tPA) is currently the only FDA-approved thrombolytic therapy for the acute treatment of ischemic stroke4. This treatment is approved for less than 10% of patients, and is given to less than 4%4. In addition, greater than 65% of hospitals in America have never administered tPA to patients due to low efficacy as well as potential harmful side effects5. Antiplatelets, such as low dose aspirin, are another treatment option. These are drugs, and therefore have negative side effects associated with long-term use such as increased risk of hemorrhagic stroke6, and gastrointestinal bleeding7. As a result, there is a distinct lack of safe therapeutic options for both the early and long-term treatment of ischemic stroke patients. Cerebrovascular collaterals refer to the network of blood vessels that are clinically documented to perfuse stroke-affected tissue during ischemic stroke and reduce brain injury8. While strategies to improve collateral blood flow during stroke are of significant therapeutic interest, mechanisms and a means to improve circulation through these blood vessels during stroke remain unknown. This honors thesis proposal rests on a key in vivo observation that supplementation of a lesser-characterized natural vitamin E, alpha-tocotrienol (TCT), improves cerebrovascular collateral blood flow and attenuates stroke injury8. TCT therefore serves as a powerful tool to study cerebrovascular collateral remodeling during stroke. The overall objective of this honors thesis will be to characterize the effects of TCT on cerebrovascular collateral perfusion during stroke and to identify a mechanistic basis for TCT improvement of cerebrovascular collateral circulation. Many previously identified arteriogenic markers, including Tissue inhibitor of metalloproteinase 1 (TIMP1), will be investigated as a known molecular target of interest for induction of collateral growth in the brain. FITC-lectin tagging of cerebrovascular collaterals will be used for laser capture microdissection experiments and downstream molecular study of arteriogenic targets. This approach will enable the specific collection of perfused cerebrovascular collaterals from stroke-affected tissue for mechanistic study.
Undergraduate Scholarship Competitions Administered by the ASC Honors Program
Academic Major: Biology
Funding from research grants awarded to Dr. Cameron Rink
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