The contribution of the cerebral microvasculature dysfunction to progressive ischemic injury after middle cerebral artery (MCA) occlusion requires investigation. Based on our preliminary data, we hypothesize that intravascular fibrin deposition contributes to progressive cerebral microvascular plasma perfusion deficit after embolic MCA occlusion, that increased levels of type 1 plasminogen activator (PAI-1) in the cerebral microvasculature contribute to stabilization of fibrin deposition and that intra-arterial administration of TNK-tPA, a thrombolytic agent resistant to PAI-1, to embolic ischemic rats accelerates recanalization of occluded cerebral vessels, improves cerebral microvascular perfusion, reduces infarct volume and improves neurological outcome. We will test our hypotheses in our newly developed model of focal cerebral embolic ischemia which mimics human stroke. We will measure temporal and spatial profiles of cerebral microvascular plasma perfusion deficits, fibrin deposition and parenchymal cell response to microvascular plasma perfusion deficit in ischemic brain by means of three dimensional quantitative laser scanning confocal microscopy (LSCM) in combination with immunofluorescent staining. We will determine whether changes in local levels of key fibrinolytic genes, t-PA, urokinase type plasminogen activator (u-PA), and PAI-1 contribute to fibrin deposition by means of reverse transcription (RT)-polymerase chain reaction (PCR), in situ hybridization, zymography and immunohistochemistry. We will determine whether intra-arterial administration of TNK-tPA accelerates recanalization of occluded vessels in ischemic brain by comparison with intravenous administration of TNK-tPA. Recanalization rate, tissue perfusion, microvascular plasma perfusion, ischemic lesion and neurological outcome will be assessed by means of MR angiography, MRI perfusion and diffusion weighted imaging, LSCM, histopathology and a battery of behavior tests. We expect that secondary microvascular perfusion deficit caused by intravascular fibrin deposition contributes to ischemic cell damage and intra-arterial administration of TNK-tPA accelerate recanalization of occlude vessels and reduces ischemic damage. Thus, data generated from this application will enhance our understanding of the mechanisms underlying secondary microvascular perfusion deficit resulting from MCA occlusion and provide new information on the optimum route for fast, and effective recanalization of occluded vessels with TNK-tPA.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064766-04
Application #
6696961
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Goldman, Stephen
Project Start
2001-03-02
Project End
2006-04-30
Budget Start
2004-02-01
Budget End
2006-04-30
Support Year
4
Fiscal Year
2004
Total Cost
$257,041
Indirect Cost
Name
Henry Ford Health System
Department
Neurology
Type
Schools of Medicine
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Ding, Guang-Liang; Chopp, Michael; Li, Lian et al. (2014) Magnetic Resonance Imaging of Stroke in the Rat. Bo Pu Xue Za Zhi 31:116-132
Wang, Shiyang; Chopp, Michael; Nazem-Zadeh, Mohammad-Reza et al. (2013) Comparison of neurite density measured by MRI and histology after TBI. PLoS One 8:e63511
Li, Lian; Chopp, Michael; Ding, Guang Liang et al. (2012) MRI measurement of angiogenesis and the therapeutic effect of acute marrow stromal cell administration on traumatic brain injury. J Cereb Blood Flow Metab 32:2023-32
Jiang, Quan; Ewing, James R; Chopp, Michael (2012) MRI of blood-brain barrier permeability in cerebral ischemia. Transl Stroke Res 3:56-64
Wang, L; Chopp, M; Szalad, A et al. (2011) Phosphodiesterase-5 is a therapeutic target for peripheral neuropathy in diabetic mice. Neuroscience 193:399-410
Zhang, Rui Lan; Chopp, Michael; Roberts, Cindi et al. (2011) Ascl1 lineage cells contribute to ischemia-induced neurogenesis and oligodendrogenesis. J Cereb Blood Flow Metab 31:614-25
Li, Lian; Jiang, Quan; Qu, Chang Sheng et al. (2011) Transplantation of marrow stromal cells restores cerebral blood flow and reduces cerebral atrophy in rats with traumatic brain injury: in vivo MRI study. J Neurotrauma 28:535-45
Liu, Xian Shuang; Chopp, Michael; Zhang, Rui Lan et al. (2011) MicroRNA profiling in subventricular zone after stroke: MiR-124a regulates proliferation of neural progenitor cells through Notch signaling pathway. PLoS One 6:e23461
Wang, Lei; Chopp, Michael; Teng, Hua et al. (2011) Tumor necrosis factor ýý primes cerebral endothelial cells for erythropoietin-induced angiogenesis. J Cereb Blood Flow Metab 31:640-7
Ding, Guangliang; Jiang, Quan; Li, Lian et al. (2011) Longitudinal magnetic resonance imaging of sildenafil treatment of embolic stroke in aged rats. Stroke 42:3537-41

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