NEUROBIOLOGICAL SIGNIFICANCE OF AQP4 STOP CODON READTHROUGH - PROJECT SUMMARY/ABSTRACT SOLUBLE AMYLOID BETA…
Federal financial assistance recorded from USAspending. This is not a procurement contract.
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ASST_NON_R00AG061231_075 · UNIVERSITY OF TEXAS AT DALLAS · Department of Health and Human Services
Compare Multiple AI Models with SmartSoloExplore CaptureIQ IntelligenceAssistance award details
- Assistance award identifier
- ASST_NON_R00AG061231_075
- FAIN
- R00AG061231
- Recipient
- UNIVERSITY OF TEXAS AT DALLAS
- Awarding agency
- Department of Health and Human Services
- Funding agency
- Department of Health and Human Services
- Assistance listing (CFDA)
- 93.866
- Total obligated
- $726,599
- Period
- Jul 15, 2021 – Apr 30, 2024
- Fiscal year
- 2021
- Place of performance state
- TX
- Source file
- FY2021_All_Assistance_Full_20261006.zip
Description
NEUROBIOLOGICAL SIGNIFICANCE OF AQP4 STOP CODON READTHROUGH - PROJECT SUMMARY/ABSTRACT SOLUBLE AMYLOID BETA (ASS) OLIGOMERS TRIGGER TAU TANGLE FORMATION, NEURONAL CELL LOSS, SYNAPTIC DYSFUNCTION AND COGNITIVE DECLINE SEEN IN ALZHEIMER'S DISEASE (AD). THE WATER CHANNEL AQUAPORIN 4 (AQP4) IS A KEY COMPONENT OF THE ASS REMOVAL MACHINERY IN THE BRAIN, AS EVIDENCED BY ~ 55% REDUCTION IN ASS REMOVAL IN AQP4-/- MICE. SPECIFICALLY, ASTROCYTE ENDFEET-CONCENTRATED AQP4 IS SHOWN TO BE BOTH REQUIRED FOR REMOVING ASS DURING SLEEP AND PERTURBED IN AD, SUGGESTING THAT RESTORING AQP4 TO ENDFEET CAN IMPROVE THE OUTCOME OF AD. I FIND THAT THIS ENDFEET-LOCALIZED AQP4 IS A STOP CODON READTHROUGH VERSION OF AQP4. I PERFORMED RIBOSOME FOOTPRINTING (RF), DEEP-SEQUENCING OF RIBOSOME-PROTECTED MRNA FRAGMENTS, IN THE MOUSE BRAIN AND DETECTED READS MAPPING TO THE 3' UNTRANSLATED REGION OF AQP4, SUGGESTING THAT RIBOSOMES READ PAST THE STOP CODON AND MAKE A C- TERMINALLY EXTENDED VERSION OF AQP4 (AQP4X HEREAFTER). USING AN ANTIBODY AGAINST THE READTHROUGH EPITOPE, I SHOW THAT AQP4X IS EXCLUSIVE TO THE PERIVASCULAR ENDFEET, WHEREAS THE NORMAL UN-EXTENDED AQP4 IS CONFINED ELSEWHERE ALONG THE ASTROCYTE MEMBRANE. THEREFORE, THE OBJECTIVE OF THIS PROJECT IS TO DETERMINE IF AQP4 READTHROUGH ENHANCES ASS CLEARANCE AND THUS IMPROVE AD OUTCOME. I PROPOSE 3 AIMS TO MEET THIS OBJECTIVE. IN AIM 1, I WILL DETERMINE IF AQP4X HAS ALTERED EFFICACY IN ELIMINATING ASS COMPARED TO AQP4. I WILL EXPRESS EITHER AQP4X OR AQP4 USING VIRAL TRANSDUCTION IN THE HIPPOCAMPI OF APP/PS1+/- TRANSGENIC MICE, AND USE A NOVEL MICRO-IMMUNOELECTRODE TECHNOLOGY TO MEASURE THE RATE OF ASS REMOVAL FROM THE INTERSTITIAL FLUID IN LIVE MICE. NEXT, ON THE AQP4-/- NICE THAT I HAVE ACQUIRED AND AQP4NO_X MICE THAT I HAVE GENERATED, I WILL USE ELISA TO MEASURE THEIR TOTAL BRAIN ASS LEVELS, WITH OR WITHOUT VIRAL RESCUE. I WILL ALSO EXAMINE AQP4NO_X MICE FOR MEMORY AND OTHER BEHAVIORAL DEFICITS. IN AIM 2, I WILL IDENTIFY THE CHEMICAL AND GENE