Our goals are; to reduce ischemic cell damage after middle cerebral artery (MCA) occlusion in the rat by selectively blocking leukocyte adhesion molecule receptors (CD11b, LFA-1), to investigate mechanisms by which blocking these receptors reduce ischemic cell damage, and to bring to fruition magnetic resonance imaging as a non-invasive method of assessing the response of ischemic tissue to a therapeutic intervention. To accomplish these goals we will employ experiments associated with three Specific Aims.
Aim 1 : The effect of anti-(CD11b, LFA-1) monoclonal antibodies on reducing ischemic cell damage will be investigated in rats subjected to transient (2 hours) MCA occlusion. Ischemic cell damage will be measured as a function of dose and time of antibody administration. Hypothesis: A monoclonal antibody reactive with an integrin reduces ischemic cell damage will be measured as a function of dose and time of antibody administration. Hypothesis: A monoclonal antibody reactive with an integrin reduces ischemic cell damage after transient MCA occlusion.
Aim 2 : Mechanisms by which the anti-CD11b and anti-LFA-1 reactive antibodies reduce ischemic cell damage will be investigated. 2(a); We will measure and correlate the temporal profile of the extent of neutrophil infiltration into the ischemic tissue with ischemic cell damage. Hypothesis; Infiltration of leukocytes, primarily neutrophils, into the ischemic tissue precedes or is concomitant with ischemic cell damage, and contributes to ischemic cell damage after transient focal cerebral ischemia. 2 (b). We will perform quantitative autoradiographic measurements of local cerebral blood flow at time points after transient MCA occlusion. Hypothesis; Neutrophils may contribute to ischemic cell damage in reperfusion injury by reducing local cerebral blood flow. 2(c): The permeability of the blood-brain barrier (BBB) will be evaluated at various times after transient MCA occlusion. Hypothesis; Neutrophils may contribute in part to ischemic cell damage by interacting with the capillary endothelium and thereby increasing the permeability of the BBB to water and neurotoxic substances.
Aim 3 : We will employ NMR methodology (Perfusion Imaging, Diffusion Weighted Imaging (DWI), T1 & T2 Imaging) to assess the physiological changes and efficacy of the anti- integrin therapeutic intervention. Hypothesis: With effective leukocyte anti-adhesion molecule therapy, the temporal profiles and values of the apparent diffusion constant of water (ADC)w) and CBF in the ischemic tissue will be modified, and the volume of the lesion as measured by T2 weighted imaging will be reduced compared to animals without antibody.

Project Start
1997-06-01
Project End
1998-05-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
11
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Knight, R A; Nagaraja, T N; Li, L et al. (2016) A Prospective Safety Trial of Atorvastatin Treatment to Assess Rebleeding after Spontaneous Intracerebral Hemorrhage: A Serial MRI Investigation. Austin J Cerebrovasc Dis Stroke 3:
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
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
Cui, Xu; Chopp, Michael; Zacharek, Alex et al. (2013) The neurorestorative benefit of GW3965 treatment of stroke in mice. Stroke 44:153-61
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
Cui, Xu; Chopp, Michael; Shehadah, Amjad et al. (2012) Therapeutic benefit of treatment of stroke with simvastatin and human umbilical cord blood cells: neurogenesis, synaptic plasticity, and axon growth. Cell Transplant 21:845-56

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