Stroke survivors exhibit behavioral deficits and brain damage from the primary injury, which can become aggravated over time due to secondary cell death. Each year in the United States, an estimated 795,000 people suffer from stroke and therapeutic interventions are limited with only one FDA-approved drug for ischemic stroke; namely tissue plasminogen activator or tPA. Due to its narrow therapeutic window of only 4.5 hours of ischemic stroke, tPA can only be administered to approximately 5% of ischemic patients due to hemorrhagic complications. Therefore, a safe and effective therapeutic intervention is urgently needed for ischemic stroke patients. It is well recognized that acute and chronic inflammation are associated with stroke pathology. The up regulation of inflammation-associated genes may be linked to the progression of neuro-inflammation after stroke. Recent novel findings suggest that the cerebral endothelium after ischemic injury is no longer passive and can actively upregulate specific genes called stroke vasculome, including Brahma (BRM), I?B (also called NF?B inhibitor), foxfl, and ITIH-5. In addition, the up regulation of non-inflammatory genes in the stroke vasculome also has been detected, such as apcdd1, ATP2b2, and Axin2. Preclinical studies have demonstrated that transplantation of endothelial progenitor cells (EPCs) is a promising treatment because it offers a wider therapeutic window and exerts anti-inflammatory, among other neuroprotective effects, in stroke animals, but no study has directly assessed the potential of EPCs in modifying the inflammation-associated vasculome after ischemic stroke. We advance the hypothesis that anti-inflammatory effects of transplanted EPCs will attenuate the up regulation of inflammatory genes of the stroke vasculome. Our preliminary data indicate that transplantation of human EPCs produced functional recovery primarily by maintaining the integrity of the brain vasculature, specifically preserving the blood brain barrier, which otherwise was leaky after stroke. That EPCs directly exert functional effects on the vasculature gave us the impetus to examine EPC modulation of the inflammation-associated stroke vasculome. Our goal is to better understand the mechanistic role of the vasculome in determining the therapeutic pathway solicited by transplanted EPCs in regulating inflammation within the stroke vasculature. The anticipated outcome that the vasculome (i.e., down regulation of inflammation-associated stroke genes) will reflect efficacy of transplanted EPCs is highly clinically relevant in view of overwhelming clinical findings implicating that vascular risk factors significantly contribute to stroke pathology. To this end, finding a strategy directed at regulating the inflammation-associated vasculome is likely to preserve the integrity of brain vasculature, thereby improving the stroke outcome. Our specific objective in this project is to assess the functional benefit of transplanted EPCs on regulating the inflammation-associated stroke vasculome and to determine the role of specific inflammatory genes in EPC vasculome modulation.

Public Health Relevance

Stroke-induced morbidity and mortality represent a significant unmet clinical need with treatment options limited to tissue plasminogen activator, which is only effective when administered within 4.5 hours following stroke. The overall goal of this study is to test the effectiveness of endothelial progenitor cell therapy in attenuating the inflammation-associated stroke vasculome, offering a potential treatment against the secondary cell death associated with stroke, as well as providing a mechanistic insight on directed targeting of specific inflammatory genes in maintaining the patency of the vasculome towards improvement of stroke outcome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS094087-01
Application #
8993820
Study Section
Special Emphasis Panel (ZRG1-MDCN-G (05))
Program Officer
Koenig, James I
Project Start
2015-06-15
Project End
2017-05-31
Budget Start
2015-06-15
Budget End
2016-05-31
Support Year
1
Fiscal Year
2015
Total Cost
$186,875
Indirect Cost
$61,875
Name
University of South Florida
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33612
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Liska, Michael G; Crowley, Marci G; Borlongan, Cesar V (2017) Regulated and Unregulated Clinical Trials of Stem Cell Therapies for Stroke. Transl Stroke Res 8:93-103
Acosta, Sandra A; Mashkouri, Sherwin; Nwokoye, Diana et al. (2017) Chronic inflammation and apoptosis propagate in ischemic cerebellum and heart of non-human primates. Oncotarget 8:102820-102834
Marcet, Paul; Santos, Nicole; Borlongan, Cesar V (2017) When friend turns foe: central and peripheral neuroinflammation in central nervous system injury. Neuroimmunol Neuroinflamm 4:82-92
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Napoli, Eleonora; Borlongan, Cesar V (2017) Stem Cell Recipes of Bone Marrow and Fish: Just What the Stroke Doctors Ordered. Stem Cell Rev 13:192-197
Stonesifer, Connor; Corey, Sydney; Ghanekar, Shaila et al. (2017) Stem cell therapy for abrogating stroke-induced neuroinflammation and relevant secondary cell death mechanisms. Prog Neurobiol 158:94-131
Napoli, Eleonora; Borlongan, Cesar V (2017) Cell Therapy in Parkinson's Disease: Host Brain Repair Machinery Gets a Boost From Stem Cell Grafts. Stem Cells 35:1443-1445
Shojo, Hideki; Borlongan, Cesario V; Mabuchi, Tadashi (2017) Genetic and Histological Alterations Reveal Key Role of Prostaglandin Synthase and Cyclooxygenase 1 and 2 in Traumatic Brain Injury-Induced Neuroinflammation in the Cerebral Cortex of Rats Exposed to Moderate Fluid Percussion Injury. Cell Transplant 26:1301-1313
Napoli, Eleonora; Borlongan, Cesar V (2016) Recent Advances in Stem Cell-Based Therapeutics for Stroke. Transl Stroke Res 7:452-457

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