Stroke is the third leading cause of death and the leading cause of serious, long-term disability in the U.S. However, while advances have been made in acute stroke treatment, our understanding of the mechanisms underlying brain self-repair after stroke remains poor. Therefore, the problem of brain repair and stroke rehabilitation is an emerging research priority, with the underlying goal of identifying and improving brain reparative processes. Brain repair reportedly occurs in a close temporal-spatial neurovascular niche of revascularization (angiogenesis) and neuronal repopulation (neurogenesis). We hypothesize that the post-stroke brain stimulates angiogenesis and neurovascular niche formation in part by generating a bioactive fragment of the extracellular matrix (ECM), perlecan. Our hypothesis is based on several key observations including our preliminary data: Stroke results in proteolytic generation of bioactive fragments of perlecan, the most protease-sensitive ECM component studied, and perlecan is required for both angiogenesis and neurogenesis. Our preliminary studies indicate that the C-terminal fragment of perlecan, domain V (DV), a previously identified modifier of angiogenesis, 1) is upregulated in the brain after stroke, 2) enhances brain angiogenesis in vitro and in vivo, 3) increases brain endothelial cell secretion of brain derived neurotrophic factor (BDNF), an important pro-angiogenic, neuroprotective and migration promoting factor in the neurovascular niche, and 4) may exert these effects through the pro-angiogenic (5(1 integrin. Empowered by this new knowledge, we now plan to 1) Determine the role of DV in brain angiogenesis and neurovascular niche formation, 2) Determine the integrin-related signaling pathway by which DV affects brain angiogenesis and neurovascular niche formation, and 3) Determine the importance and therapeutic potential of DV to post-stroke brain repair. Specifically, we plan to demonstrate that DV stimulates brain angiogenesis and neurovascular niche formation via interaction with the (5(1 integrin and subsequent release of BDNF, and demonstrate that DV enhances post-stroke brain repair. The proposed studies are significant in that they investigates differences between brain and nonbrain angiogenesis, seek to establish a novel mechanism of post-stroke brain self-repair for therapeutic exploitation, and suggests a significantly longer therapeutic window than currently employed stroke therapies. Our investigation is innovative because it suggests that ECM fragments generated by brain injury could possess beneficial effects and identifies a novel cause of brain endothelial cell BDNF release. Our long term goal is to develop DV as a human stroke therapy.

Public Health Relevance

Stroke is the third leading cause of death and the leading cause of serious, long-term disability in the U.S. However, while advances have been made in trying to minimize brain injury after stroke, little is known about how to stimulate repair of injured brain tissue. Therefore, we propose to study the potential benefits of a stroke-generated protein fragment in a stroke animal model, with the goal of developing a new type of human stroke therapy.

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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Koenig, James I
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University of Kentucky
Anatomy/Cell Biology
Schools of Medicine
United States
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Maniskas, Michael E; Roberts, Jill M; Trueman, Rebecca et al. (2018) Intra-arterial nitroglycerin as directed acute treatment in experimental ischemic stroke. J Neurointerv Surg 10:29-33
Roberts, Jill; de Hoog, Leon; Bix, Gregory J (2017) Mice deficient in endothelial ?5 integrin are profoundly resistant to experimental ischemic stroke. J Cereb Blood Flow Metab 37:85-96
Jullienne, Amandine; Roberts, Jill M; Pop, Viorela et al. (2014) Juvenile traumatic brain injury induces long-term perivascular matrix changes alongside amyloid-beta accumulation. J Cereb Blood Flow Metab 34:1637-45
Parham, Christi; Auckland, Lisa; Rachwal, Jessica et al. (2014) Perlecan domain V inhibits amyloid-? induced brain endothelial cell toxicity and restores angiogenic function. J Alzheimers Dis 38:415-23
Bix, Gregory J; Gowing, Emma K; Clarkson, Andrew N (2013) Perlecan domain V is neuroprotective and affords functional improvement in a photothrombotic stroke model in young and aged mice. Transl Stroke Res 4:515-23
Kahle, Michael P; Bix, Gregory J (2012) Successfully Climbing the ""STAIRs"": Surmounting Failed Translation of Experimental Ischemic Stroke Treatments. Stroke Res Treat 2012:374098
Roberts, Jill; Kahle, Michael P; Bix, Gregory J (2012) Perlecan and the blood-brain barrier: beneficial proteolysis? Front Pharmacol 3:155
Clarke, Douglas N; Al Ahmad, Abraham; Lee, Boyeon et al. (2012) Perlecan Domain V induces VEGf secretion in brain endothelial cells through integrin ?5?1 and ERK-dependent signaling pathways. PLoS One 7:e45257
Saini, Maxim G; Bix, Gregory J (2012) Oxygen-glucose deprivation (OGD) and interleukin-1 (IL-1) differentially modulate cathepsin B/L mediated generation of neuroprotective perlecan LG3 by neurons. Brain Res 1438:65-74
Kahle, Michael P; Lee, Boyeon; Pourmohamad, Tony et al. (2012) Perlecan domain V is upregulated in human brain arteriovenous malformation and could mediate the vascular endothelial growth factor effect in lesional tissue. Neuroreport 23:627-30

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