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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS061954-03
Application #
7798019
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Jacobs, Tom P
Project Start
2008-04-01
Project End
2013-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
3
Fiscal Year
2010
Total Cost
$317,265
Indirect Cost
Name
West Virginia University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26506
Tan, Zhenjun; Lucke-Wold, Brandon P; Logsdon, Aric F et al. (2015) Bryostatin extends tPA time window to 6 h following middle cerebral artery occlusion in aged female rats. Eur J Pharmacol 764:404-12
Robson, Matthew J; Turner, Ryan C; Naser, Zachary J et al. (2014) SN79, a sigma receptor antagonist, attenuates methamphetamine-induced astrogliosis through a blockade of OSMR/gp130 signaling and STAT3 phosphorylation. Exp Neurol 254:180-9
VanGilder, Reyna L; Davidov, Danielle M; Stinehart, Kyle R et al. (2014) C-reactive protein and long-term ischemic stroke prognosis. J Clin Neurosci 21:547-53
Lucke-Wold, Brandon P; Logsdon, Aric F; Turner, Ryan C et al. (2014) Aging, the metabolic syndrome, and ischemic stroke: redefining the approach for studying the blood-brain barrier in a complex neurological disease. Adv Pharmacol 71:411-49
Turner, Ryan C; VanGilder, Reyna L; Naser, Zachary J et al. (2014) Elucidating the severity of preclinical traumatic brain injury models: a role for functional assessment? Neurosurgery 74:382-94; discussion 394
Lucke-Wold, Brandon Peter; Turner, Ryan Coddington; Logsdon, Aric Flint et al. (2014) Linking traumatic brain injury to chronic traumatic encephalopathy: identification of potential mechanisms leading to neurofibrillary tangle development. J Neurotrauma 31:1129-38
Meyer, Douglas A; Torres-Altoro, Melissa I; Tan, Zhenjun et al. (2014) Ischemic stroke injury is mediated by aberrant Cdk5. J Neurosci 34:8259-67
Turner, Ryan C; Dodson, Sean C; Rosen, Charles L et al. (2013) The science of cerebral ischemia and the quest for neuroprotection: navigating past failure to future success. J Neurosurg 118:1072-85
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
Tan, Zhenjun; Turner, Ryan C; Leon, Rachel L et al. (2013) Bryostatin improves survival and reduces ischemic brain injury in aged rats after acute ischemic stroke. Stroke 44:3490-7

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