Age is the single greatest risk factor for stroke;yet most stroke models use younger animals. Stroke involves changes in the cerebrovasculature;yet research is predominantly focused on therapeutics that protect neurons. These incongruities in stroke research may, in part, explain the failure of successful neuroprotectants in animal studies to translate into clinically effective therapies. We argue that by not accounting for age and focusing on changes in the cerebrovasculature, the stroke community has overlooked a vast area of potential therapeutic growth. Neuropoietic cytokines play a primary role in the complex relationship between aging and chronic morbidity;yet, little attention has been focused on age- related changes in neuropoietic cytokine activity in the brain. The blood-brain barrier (BBB) is the functional element of the neurovascular unit, an extensive network comprised of endothelium, glia, pericytes, neurons, and extracellular matrix. The BBB partitions the systemic circulation from the brain parenchyma and serves to establish, maintain, and regulate discrete environments within the brain for optimal neuronal function. The proposed studies address priorities outlined in the NINDS Stroke Progress Review Group and speak to the missions of both NINDS and NIA. Our long term goal is to improve functional outcomes of people who have a stroke. Our central hypothesis states age contributes to changes in neuropoietic cytokine signaling resulting in an early, exacerbated disruption of the BBB followed by attenuated vascular recovery after ischemic stroke and reperfusion. We will test our central hypothesis with three specific aims.
Specific aim 1 will determine changes in neuropoietic cytokine signaling at the neurovascular unit in aged rats following stroke/reperfusion injury.
Specific Aim 2 will investigate changes in neuropoietic cytokine signaling on size and localization of BBB disruption in aged rats following stroke/reperfusion injury.
Specific Aim 3 will assess changes in neuropoietic cytokine signaling on cerebral microvasculature recovery in aged rats following stroke/reperfusion injury. We expect the results from this proposal will clearly highlight that aging has profound effects on neuropoietic signaling that influences neurovascular cell-cell communication and BBB function following stroke that must be taken into account when developing and screening therapeutics to reduce morbidity and mortality.

Public Health Relevance

In the United States, stroke is the third leading cause of death and the leading cause of disability;yet effective treatments for people suffering a stroke have not materialized. We contend that age is the single most important risk factor for stroke but most stroke research is being conducted on young animals. Furthermore, most stroke research is focused on rescuing and protecting neurons;yet, stroke is a vascular disease. This grant proposal is designed to evaluate the influence aging has on BBB function following ischemia and reperfusion. Our results will lead to a better understanding of the role age, plays in stroke etiology, progression, and recovery.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Bosetti, Francesca
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West Virginia University
Schools of Pharmacy
United States
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Robson, Matthew J; Turner, Ryan C; Naser, Zachary J et al. (2013) SN79, a sigma receptor ligand, blocks methamphetamine-induced microglial activation and cytokine upregulation. Exp Neurol 247:134-42
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VanGilder, Reyna L; Huber, Jason D; Rosen, Charles L et al. (2012) The transcriptome of cerebral ischemia. Brain Res Bull 88:313-9
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