The target for ischemic injury in the early moments of ischemic stroke is the microvasculature. Occlusion of cerebral microvessels by polymorphonuclear (PMN) leukocytes, platelets, and/or fibrin occurs in the ischemic regions. These events involve a fraction of the microvasculature, so that it has been postulated that microvessel occlusion caused when flow ceases in the middle cerebral artery (MCA) contributes to neuron injury by local ischemia. Secondary forms of injury (e.g., inflammation) initiated at the microvasculature are responsible for subsequent tissue injury. The purpose of this project has been to examine the mechanisms by which ischemia induces acute development of microvascular occlusions in experimental stroke. A refinement of the hypothesis to be tested states that focal cerebral ischemia accompanying MCA occlusion in the nonhuman primate i) causes microvascular obstruction due to activation of the microvascular endothelium, PMN leukocytes, platelets and coagulation; ii) increases the density of injured neurons and nonneuronal cells due to microvessel occlusion; and iii) alters the frequency and extent of hemorrhagic transformation. In addition, it is proposed that measures which are known to decrease microvascular obstruction can decrease neuronal injury and improve outcome.
The Specific Aims are to 1) quantitate the relationship between normal microvessels and neurons within the non-ischemic and ischemic basal ganglia, 2) quantitate the relationship of proximal neuron injury and microvessel events including platelet deposition, fibrin formation and PMN leukocyte adhesion at 2 hours after MCA occlusion, 3) quantitate the relationship of neuron injury to microvessel activation depicted by PCNA, VEGF or complement expression, and 4) quantitate the contribution of platelets, fibrin, and PMN leukocytes (which constitute acute microvascular occlusions) directly to neuron injury or to secondary cell injury following MCA occlusion.
Aim 1 will develop normalized data relating microvessels to neurons in the non-ischemic and ischemic basal ganglia.
Aims 2 and 3 will establish the relationships of microvessel occlusion and activation to neuron injury.
Aim 4 will test the contributions of microvessel occlusion directly to neuron injury, or to secondary injury. These studies are a direct extension of completed work of this proposal, and are expected to add greatly to the understanding of how vascular ischemia affects neuron integrity with testable treatment strategies.
| Del Zoppo, Gregory J (2013) Toward the neurovascular unit. A journey in clinical translation: 2012 Thomas Willis Lecture. Stroke 44:263-9 |
| Muldoon, Leslie L; Alvarez, Jorge I; Begley, David J et al. (2013) Immunologic privilege in the central nervous system and the blood-brain barrier. J Cereb Blood Flow Metab 33:13-21 |
| del Zoppo, Gregory J; Izawa, Yoshikane; Hawkins, Brian T (2013) Hemostasis and alterations of the central nervous system. Semin Thromb Hemost 39:856-75 |
| del Zoppo, Gregory J (2013) Plasminogen activators and ischemic stroke: conditions for acute delivery. Semin Thromb Hemost 39:406-25 |
| del Zoppo, Gregory J; Frankowski, Harald; Gu, Yu-Huan et al. (2012) Microglial cell activation is a source of metalloproteinase generation during hemorrhagic transformation. J Cereb Blood Flow Metab 32:919-32 |
| Frankowski, Harald; Gu, Yu-Huan; Heo, Ji Hoe et al. (2012) Use of gel zymography to examine matrix metalloproteinase (gelatinase) expression in brain tissue or in primary glial cultures. Methods Mol Biol 814:221-33 |
| del Zoppo, Gregory J; Sharp, Frank R; Heiss, Wolf-Dieter et al. (2011) Heterogeneity in the penumbra. J Cereb Blood Flow Metab 31:1836-51 |
| Osada, Takashi; Gu, Yu-Huan; Kanazawa, Masato et al. (2011) Interendothelial claudin-5 expression depends on cerebral endothelial cell-matrix adhesion by ?(1)-integrins. J Cereb Blood Flow Metab 31:1972-85 |
| del Zoppo, Gregory J (2010) Acute anti-inflammatory approaches to ischemic stroke. Ann N Y Acad Sci 1207:143-8 |
| del Zoppo, Gregory J (2010) Plasminogen activators in ischemic stroke: introduction. Stroke 41:S39-41 |
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