This is an application for a competitive supplement to the three-year Mentored Clinical Scientist Development (K08) Award. The original K08 grant entitled, """"""""The role of zinc in focal ischemic brain injury,"""""""" was awarded on 7/1/00. However, in 12/01 (1.5 years into the grant), the applicant's mentor, Dr. Dennis Choi left the institution, prompting a change in mentors (to Dr. Chung Y. Hsu, with co-mentors, Dr. Mark Goldberg and Dr. David Holtzman) and a change in research direction. For the past 9 months, the applicant has been pursuing this new direction, studying the pathogenesis of spontaneous intracerebral hemorrhage in cerebral amyloid angiopathy (CAA). In particular, he has found that the amyloid beta peptide induces the expression and activity of the extracellular matrix-degrading protease, matrix metalloproteinase-9 (MMP-9), in cultures of cerebral endothelial cells. Furthermore, vascular MMP-9-like immunoreactivity was found in aged mice carrying the double Swedish mutation of the amyloid precursor protein (APPsw, a rodent model of CAA), but not in younger mice. The central hypothesis of this proposal is that amyloid beta, which accumulates in cerebral blood vessels in CAA, induces vascular MMP-9 activity and contributes to the development of spontaneous hemorrhagic stroke. Due to space limitations a complete application detailing the new proposal is not possible; however, Specific Aims, preliminary studies, and a brief outline of research design is included in this proposal. The goal of the applicant during this extension is to pursue the project outlined above and to receive additional training in molecular biology, microscopy and in developing animal models for disease. The additional two years of funding will allow protected time to accumulate data and publications that will put the applicant in a position to apply for independent funding (R21 or R01) and, ultimately, develop into an independent investigator.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS002190-05
Application #
6779952
Study Section
NST-2 Subcommittee (NST)
Program Officer
Jacobs, Tom P
Project Start
2000-09-25
Project End
2005-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
5
Fiscal Year
2004
Total Cost
$124,468
Indirect Cost
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Yin, Ke-Jie; Hsu, Chung Y; Hu, Xiao-Yan et al. (2006) Protein phosphatase 2A regulates bim expression via the Akt/FKHRL1 signaling pathway in amyloid-beta peptide-induced cerebrovascular endothelial cell death. J Neurosci 26:2290-9
Xiao, Qingli; Hsu, Chung Y; Chen, Hong et al. (2005) Characterization of cis-regulatory elements of the vascular endothelial growth inhibitor gene promoter. Biochem J 388:913-20
Yin, Ke-Jie; Lee, Jin-Moo; Chen, Hong et al. (2005) Abeta25-35 alters Akt activity, resulting in Bad translocation and mitochondrial dysfunction in cerebrovascular endothelial cells. J Cereb Blood Flow Metab 25:1445-55
Hartman, Richard E; Lee, Jin M; Zipfel, Greg J et al. (2005) Characterizing learning deficits and hippocampal neuron loss following transient global cerebral ischemia in rats. Brain Res 1043:48-56
Lee, Jin-Moo; Yin, Ke-Jie; Hsin, Idar et al. (2003) Matrix metalloproteinase-9 and spontaneous hemorrhage in an animal model of cerebral amyloid angiopathy. Ann Neurol 54:379-82
Lee, J-M; Zipfel, G J; Park, K H et al. (2002) Zinc translocation accelerates infarction after mild transient focal ischemia. Neuroscience 115:871-8