Stroke remains a major problem for public health in the United States. There are at least three human alleles for apolipoprotein E (2, 3, or 4). Recent evidence indicates that the patient's genotype for apolipoprotein E (Apo E) is a risk factor for poor outcome from central nervous system injury. Patients undergoing cardiopulmonary bypass surgical procedures, and those recovering form intracranial hemorrhagic stroke or head trauma have poorer neurologic outcomes if they carry the apo E4 allele. Little is known regarding potential interactions between Apo E and mechanisms of ischemic brain damage. Using a recovery model of temporary middle cerebral artery occlusion, this research will examine mice deficient for Apo E and genetically engineered mice carrying different alleles of human Apo E. Two distinctly different strains have been created which express the human Apo E isoforms. both carry the human DNA sequence coding for the Apo E protein. One strain utilizes the human transgenic Apo E promoter while the other utilizes the native murine promoter. Mice carrying the human promoter demonstrate Apo E immunoreactivity in both neurons and glial (similar to the pattern observed in humans). Mice carrying the murine promoter stain positive for Apo E only in glia (similar to the pattern observed in wild type rodents). We propose to define: 1) If these mutant mice exhibit a differential frequency of gross anomalies in the cerebral vasculature; 2) If human Apo E4 causes a dose dependent effect on murine focal ischemic outcome; 3)If there is a difference in cerebral infarct size attributable to the Apo E genotype; 4) If allele specific differences in ischemic outcome ar attributable to differences in volume of tissue at risk for infarction during the ischemic insult; 5) If the effect of ApoE on stroke is mediated via central nervous system expression or from the periphery; 6) If pre-ischemic intraneuronal expression of Apo E is required for differential effects of the Apo alleles on ischemic outcome; 8) If Apo E immunoreactivity in neurons and glia in the penumbra of a focal ischemic lesion varies as a result of the Apo E allele; and 9) If the human Apo E allele alters the apoptotic response to brief focal ischemic insults. We believe that this information would be of substantial value in defining both the relevance of Apo E mechanisms to ischemic outcome and provide a basis for therapeutic approaches to the treatment of stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037235-02
Application #
2873225
Study Section
Special Emphasis Panel (ZRG1-NLS-3 (01))
Program Officer
Jacobs, Tom P
Project Start
1998-02-01
Project End
2002-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Duke University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Aono, M; Bennett, E R; Kim, K S et al. (2003) Protective effect of apolipoprotein E-mimetic peptides on N-methyl-D-aspartate excitotoxicity in primary rat neuronal-glial cell cultures. Neuroscience 116:437-45
Lynch, John R; Pineda, Jose A; Morgan, Duncan et al. (2002) Apolipoprotein E affects the central nervous system response to injury and the development of cerebral edema. Ann Neurol 51:113-7
Aono, Mitsuo; Lee, Yoonki; Grant, Elfrida R et al. (2002) Apolipoprotein E protects against NMDA excitotoxicity. Neurobiol Dis 11:214-20
Wellons 3rd, J C; Sheng, H; Laskowitz, D T et al. (2000) A comparison of strain-related susceptibility in two murine recovery models of global cerebral ischemia. Brain Res 868:14-21
Sheng, H; Laskowitz, D T; Mackensen, G B et al. (1999) Apolipoprotein E deficiency worsens outcome from global cerebral ischemia in the mouse. Stroke 30:1118-24
Sheng, H; Laskowitz, D T; Pearlstein, R D et al. (1999) Characterization of a recovery global cerebral ischemia model in the mouse. J Neurosci Methods 88:103-9
Sheng, H; Bart, R D; Oury, T D et al. (1999) Mice overexpressing extracellular superoxide dismutase have increased resistance to focal cerebral ischemia. Neuroscience 88:185-91
Bart, R D; Sheng, H; Laskowitz, D T et al. (1998) Regional CBF in apolipoprotein E-deficient and wild type mice during focal cerebral ischemia. Neuroreport 9:2615-20
Sheng, H; Laskowitz, D T; Bennett, E et al. (1998) Apolipoprotein E isoform-specific differences in outcome from focal ischemia in transgenic mice. J Cereb Blood Flow Metab 18:361-6