The applicants propose a highly integrated application focused on preclinical and clinical studies to investigate and develop treatment of stroke with an anti-platelet aggregation agent alone, and in combination with thrombolysis using recombinant tissue plasminogen activator (rtPA). Permeating this Program is the development and application of MRI to enhance the management of the stroke patient. Three interdependent Projects and two Cores constitute this grant application. Project 1, Anti-Platelet Aggregation Therapy for Embolic Stroke, will investigate the mechanisms promoting secondary thrombosis after embolic stroke and treatment with rtPA in rat, and will test, in a controlled experimental model, treatment of embolic stroke with an antibody against the GPIIb/IIIa receptor. This receptor binds the platelet to fibrin and is responsible for platelet aggregation and therefore, platelet mediated thrombosis. This project leads into Project 2, MR Assessment of Transient Cerebral Ischemia, which develops and applies a multi-parameter MRI model to experimental embolic stroke in rats. The goals of this Project are to develop and test the application of the multi-parameter MRI model to identify candidates for therapy and to exclude candidates from therapy after embolic stroke. In addition, the MRI response to thrombolysis with rtPA and rtPA in combination with an antagonist to platelet aggregation will be tested. Projects 1 and 2 form the preclinical support for a Phase II Pilot Clinical Trial of treatment of stroke with an anti-platelet aggregation agent, abciximab. This Project will test activity of treatment of the stroke patient with abciximab and will identify an MRI based surrogate marker for activity and accrue MR data to select patients for anti-platelet aggregation therapy. Core A is an Administrative and Biostatistical Core. Core B, the MRI core, services all three Projects. The Program Project provides an integrated highly coherent effort to enhance management and therapeutic intervention in the treatment of acute stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS023393-16
Application #
6660681
Study Section
Special Emphasis Panel (ZNS1-SRB-W (01))
Program Officer
Jacobs, Tom P
Project Start
1986-04-01
Project End
2006-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
16
Fiscal Year
2003
Total Cost
$1,388,360
Indirect Cost
Name
Henry Ford Health System
Department
Dermatology
Type
Schools of Medicine
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
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Pindolia, Kirit; Li, Hong; Cardwell, Cisley et al. (2014) Characterization and functional analysis of cellular immunity in mice with biotinidase deficiency. Mol Genet Metab 112:49-56
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Zhang, Rui Lan; Zhang, Zheng Gang; Chopp, Michael (2013) Targeting nitric oxide in the subacute restorative treatment of ischemic stroke. Expert Opin Investig Drugs 22:843-51
Yan, Tao; Chopp, Michael; Ning, Ruizhuo et al. (2013) Intracranial aneurysm formation in type-one diabetes rats. PLoS One 8:e67949
Hernández-Vázquez, A; Wolf, B; Pindolia, K et al. (2013) Biotinidase knockout mice show cellular energy deficit and altered carbon metabolism gene expression similar to that of nutritional biotin deprivation: clues for the pathogenesis in the human inherited disorder. Mol Genet Metab 110:248-54
Xiong, Ye; Mahmood, Asim; Chopp, Michael (2013) Animal models of traumatic brain injury. Nat Rev Neurosci 14:128-42
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
Santra, Manoranjan; Chopp, Michael; Zhang, Zheng Gang et al. (2012) Thymosin ? 4 mediates oligodendrocyte differentiation by upregulating p38 MAPK. Glia 60:1826-38

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