UNCOVERING CELL FACTORS WITH AGGREGATE CLEARANCE ACTIVITY BY SCALABLE INDUCED PROXIMITY - SUMMARY TOXIC AGG…
Federal financial assistance recorded from USAspending. This is not a procurement contract.
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ASST_NON_R00AG075256_075 · RUTGERS THE STATE UNIVERSITY OF NEW JERSEY · Department of Health and Human Services
Compare Multiple AI Models with SmartSoloExplore CaptureIQ IntelligenceAssistance award details
- Assistance award identifier
- ASST_NON_R00AG075256_075
- FAIN
- R00AG075256
- Recipient
- RUTGERS THE STATE UNIVERSITY OF NEW JERSEY
- Awarding agency
- Department of Health and Human Services
- Funding agency
- Department of Health and Human Services
- Assistance listing (CFDA)
- 93.866
- Total obligated
- $497,998
- Period
- Sep 15, 2022 – Dec 31, 2027
- Fiscal year
- 2025
- Place of performance state
- NJ
- Source file
- FY2025_All_Assistance_Full_20261006.zip
Description
UNCOVERING CELL FACTORS WITH AGGREGATE CLEARANCE ACTIVITY BY SCALABLE INDUCED PROXIMITY - SUMMARY TOXIC AGGREGATION OF PROTEINS IS A PATHOGENIC MECHANISM IN NEURODEGENERATIVE DISEASE (ND). PROTEINS SUCH AS TDP-43 IN FRONTOTEMPORAL DEMENTIA (FTD) OR ALZHEIMERâS DISEASE (AD) MISFOLD INTO AGGREGATES, WHICH BOTH DISRUPTS ENDOGENOUS PROTEIN FUNCTIONS AND CONFERS TOXIC NEW FUNCTIONS THAT LEAD TO NEURONAL CELL DEATH. THERE ARE NO CURES FOR AD OR FTD, BUT CURRENT RESEARCH SUGGESTS AGGREGATE CLEARANCE IS A PROMISING THERAPEUTIC STRATEGY. AGGREGATES OF TDP-43 ARE INFLUENCED BY THE PROTEOSTASIS NETWORK CONSISTING OF CHAPERONES AND DEGRADATION MACHINERY, THOUGH WHICH FACTORS CAN MEDIATE AGGREGATE CLEARANCE AND HOW THEY DO SO IS NOT KNOWN. PRIOR WORK USING SMALL MOLECULE LIGANDS CALLED PROTACS TO INDUCE PROXIMITY OF TARGET PROTEINS TO COMPONENTS OF THE UBIQUITIN-PROTEASOME SYSTEM HAS PROVEN A PROMISING APPROACH FOR CLEARING ABERRANT PROTEIN SPECIES. ANALOGOUSLY, THIS PROPOSAL AIMS TO SYSTEMATICALLY SCREEN THE LARGE, UNINTERROGATED PORTION OF THE PROTEOSTASIS NETWORK FOR ITS ABILITY TO CLEAR AGGREGATES OF TDP-43 BY LIGAND-INDUCED PROXIMITY. IN ADDITION TO PROTEINS THAT MAY FUNCTION AS DEGRADERS OR DISAGGREGASES, RNAS WILL ALSO BE SCREENED FOR AGGREGATE CLEARANCE ACTIVITY. THIS WORK WILL REVEAL NEW QUALITY CONTROL FACTORS AND MECHANISMS INVOLVED IN AGGREGATE CLEARANCE AND WILL PROVIDE A PLATFORM FOR TRANSLATIONAL DEVELOPMENT OF MULTISPECIFIC DRUGS FOR ND. THIS WORK WILL BE ACCOMPLISHED IN THREE AIMS, PROVIDING ME WITH CRITICAL TRAINING FOR TRANSITION INTO INDEPENDENT RESEARCH. IN AIM 1, I WILL DEVELOP AN EXPERIMENTAL WORKFLOW TO IMAGE AGGREGATE-PRONE TDP-43 EXPRESSED IN A MULTIPLEXED TAG CELL LIBRARY. I WILL WRITE COMPUTATIONAL PIPELINES TO CHARACTERIZE MECHANISMS OF AGGREGATE CLEARANCE AND INTEGRATE THEM WITH AUTOMATED IN-SITU SEQUENCING TO REVEAL THE IDENTITY OF THE PUTATIVE EFFECTOR IN EACH CELL. THIS AIM WILL OPTIMIZE REAGENTS AND DEVELOP ANALYSIS METHODS FOR INDUCED PROXI