Discovery of Novel Therapeutic Targets
Insights into the mechanistic basis of Alzheimer's disease and other neurodegenerative diseases have historically derived from molecular genetic analysis of familial forms of these disorders. Mayo Clinic in Florida is a world leader in this area.
One of the most far-reaching fruits of the genomic revolution is the development of genome-scale collections of full-length human cDNAs and siRNAs. These novel reagents — the enormous potential of which has only begun to be tapped — can be used in appropriately designed high-throughput screening campaigns to discover novel genes affecting disease processes.
The laboratory of Malcolm A. Leissring, Ph.D., has developed cell-based functional assays that can be used in tandem with genome-scale genetic perturbagens to discover novel genes influencing known pathogenic processes. For example, the lab developed a sensitive and versatile fluorescence polarization-based amyloid-beta (Aβ) degradation assay that is high-throughput screening-compatible and suitable for use in cells (see figure).
Dr. Leissring's lab is currently using this assay and other Aβ quantification assays to interrogate genome-scale collections of cDNAs and siRNAs in search of proteases and other proteins that influence the catabolism of Aβ. These assays hold enormous promise for discovering new genes that — once validated in animal models — could represent novel therapeutic targets for combating Alzheimer's disease.
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