Our ultimate goal is to use newly discovered compounds directed to
APP-mRNA 5'UTR to limit A(3-peptide output in cell culture systems,
and subsequently to therapeutically test these compounds in transgenic
mouse models for APP and A(3 over-expression. We have developed a
collaboration with Dr. Steve Gullans (Director of Renal Division
Research, Harvard Institutes of Medicine).
During the course of this project, we have started a screen for APP 5'UTR-binding compounds from a unique library of 1,500 FDA preapproved drugs arranged in a convenient format for transferring to cells growing in 96 well plates. Using a new transfection-based assay, in which APP-5'UTR sequences drive the expression of luciferase and green fluorescent protein (GFP) reporter genes, our two laboratories are conducting a screen to identify new "hits" of therapeutic compounds that already have FDA approval.
Single lead drugs, or more potent combinations, will be tested for their capacity to suppress APP translation by RNA targeting. In conducting these screens, great care has to be taken to ensure that lead compounds do not alter APLP-1 and APLP-2 and ferritin gene expression.
This serves as a screening control designed to minimize side effects. New and powerful combinations of FDA-approved drugs will soon be available as therapy for AD patients to use at low doses. Their efficacy will be directed to suppress APP translation, an effect that subsequently would reduce neurotoxic production of A(3-peptide..
During the course of this project, we have started a screen for APP 5'UTR-binding compounds from a unique library of 1,500 FDA preapproved drugs arranged in a convenient format for transferring to cells growing in 96 well plates. Using a new transfection-based assay, in which APP-5'UTR sequences drive the expression of luciferase and green fluorescent protein (GFP) reporter genes, our two laboratories are conducting a screen to identify new "hits" of therapeutic compounds that already have FDA approval.
Single lead drugs, or more potent combinations, will be tested for their capacity to suppress APP translation by RNA targeting. In conducting these screens, great care has to be taken to ensure that lead compounds do not alter APLP-1 and APLP-2 and ferritin gene expression.
This serves as a screening control designed to minimize side effects. New and powerful combinations of FDA-approved drugs will soon be available as therapy for AD patients to use at low doses. Their efficacy will be directed to suppress APP translation, an effect that subsequently would reduce neurotoxic production of A(3-peptide..
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