Projects and Grants per year
Grants and Contracts Details
Description
The supplemental studies proposed in this application derive directly from gene microarray and behavioral
analyses in the parent grant that have identified cholesterol synthesis and transport pathways in the
hippocampus as potential therapeutic targets against cognitive decline in normal aging and incipient
Alzheimer's disease (AD). Although cholesterol dysregulation has been previously linked to AD, many
questions remain unresolved and almost nothing is known regarding its role in normal aging-related
cognitive decline. To validate these targets through direct molecular interventions, we propose a series of
cholesterol pathway gene silencing/knockdown studies using interfering RNAs (iRNA) encoded in viral
vectors. One set of studies will be conducted in hippocampal cell culture and one set will be conducted in
vivo, in an aging rat model, using microsyringe delivery of viral vectors to the hippocampus. Four months
after iRNA delivery in vivo, animals will be tested for degree of cognitive impairment, and their brains will be
processed for gene microarray and immunohistochemical testing. Extensive bioinformatic analyses will then
compare the results against our large databases of aging/AD marker genes and past behavioral data to
determine whether knockdown of any cholesterol pathway gene selectively influenced genomic, cognitive
or immunohistochemical aging/AD biomarker profiles to an extent much greater than expected by random
chance. If so, this will provide strong indication that alterations in cholesterol pathways not only correlate
with, but can also regulate the progression of brain and cognitive changes in aging/AD.
These will be the first studies manipulating multiple brain cholesterol pathway genes in combination with
systematic assessment of brain aging/AD biomarkers. Evidence of modification of these biomarkers by
selective gene knockdown will provide important preclinical validation of cholesterol pathway genes as
therapeutic targets. Moreover, because gene manipulation in the brain with viral vectors is already being
investigated in human studies, results of the proposed studies might have direct implications for clinical
trials.
Status | Finished |
---|---|
Effective start/end date | 12/2/98 → 8/31/10 |
Funding
- National Institute on Aging
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Projects
- 1 Finished
-
Calcium Regulation in Brain Aging and Alzheimer's Disease - Core A
Landfield, P. (PI), Blalock, E. (CoI), Butterfield, D. A. (CoI), Chen, K. (CoI), Geddes, J. (CoI), Guttmann, R. (CoI), Kaetzel, D. (CoI), Kraner, S. (CoI), Porter, N. (CoI), St Clair, D. (CoI), Stromberg, A. (CoI), Sullivan, P. (CoI) & Thibault, O. (CoI)
12/2/98 → 8/31/10
Project: Research project