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Uncovering cell factors with aggregate clearance activity by scalable induced proximity

Award Number: R00AG075256
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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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 Alzheimer’s 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 proximity screens, training me in models of ND and pooled image analysis. In Aim 2, I will focus on screening proteostasis network components by scalable induced proximity and validate factors mediating aggregate clearance in neurons and in vitro, gaining training in cell biology and biochemical techniques to characterize degraders and disaggregases. This work will uncover recruitable factors inducing aggregate clearance. In Aim 3, as an independent investigator, I will develop pooled tagging of transcripts and use the resulting multiplexed cell libraries to screen for RNAs with induced proximity-based aggregate clearance activity. The outcome of this work will systematically characterize the proteostatic potential of RNAs in modulating aggregation and greatly expand the space of recruitable effectors with potential therapeutic benefit. The expert mentoring team I have assembled, as well as the excellent training environment at CHOP and Penn, will greatly facilitate my research and training during the mentored phase of this proposal and provide me with the skills necessary to begin independent research systematically characterizing proteostasis mechanisms involved in ND-associated protein aggregation.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $224,099 )
2026	2026	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Aging Research	000	4	12/26/2025	NON-COMPETING CONTINUATION	$224,099
														Subtotal = $224,099

Issue Date FY: 2025 ( Subtotal = $248,999 )
2025	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Aging Research	002	3	7/30/2025	EXTENSION WITH OR WITHOUT FUNDS	$24,898
2025	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Aging Research	000	3	12/31/2024	EXTENSION WITH OR WITHOUT FUNDS	$248,999
2025	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Aging Research	001	3	5/9/2025	EXTENSION WITH OR WITHOUT FUNDS	-$24,898
														Subtotal = $248,999

Grand Total All Awards = $473,098

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Uncovering cell factors with aggregate clearance activity by scalable induced proximity

Award Number: R00AG075256

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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