Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Developing innovative small-molecule lysosomal degraders for pathogenic protein aggregates in human disease

Award Number: F31NS149735
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2026
PERIOD OF PERFORMANCE END DATE: 11/30/2029

Group Awards By:

View Award Description

Developing innovative small-molecule lysosomal degraders for pathogenic protein aggregates in human disease - ABSTRACT Protein aggregate formation is a central pathogenic mechanism underlying many diseases, yet remains largely undruggable, representing a major bottleneck for current therapeutic interventions. Targeted protein degradation (TPD) is an emergent, small molecule therapeutic approach that harnesses native cellular degradation pathways to eliminate disease-causing proteins. Small molecule proteolysis-targeting chimeras (PROTACs) recruit E3 ligases to a target protein that becomes ubiquitinated for proteasomal destruction. With over 25 PROTACs currently in clinical cancer trials, the promise of this field to revolutionize modern medicine is evident but limited by the capacity of proteasomes. PROTACs utilize the proteasome, which is limited for aggregates, and lacks tissue-specificity due to the ubiquitous expression of E3 ligases. Our goals aim to develop a novel approach to eliminate disease-causing aggregates. We developed a small-molecule technology, Methyl arginine Targeting Chimera (MrTAC), which leverages proximity-induced degradation of proteins in lysosomes, which are uniquely equipped for the turnover of large protein assemblies and whole organelles. Recent work shows that arginine methylation modifications direct proteins to lysosomes during normal homeostatic maintenance in unmodified, natural conditions. Advantageously, MrTAC exploits arginine-methylation, an endogenous post-translational degradative modification for lysosomes by recruiting protein arginine methyltransferase enzymes (PRMTs) to catalyze this lysosomal-targeting modification on substrates. Dysregulation at the protein level underlies a wide range of human diseases, highlighting the potential of targeted protein degradation as a transformative therapeutic approach. Neurodegeneration is driven at the protein-level, suggesting that targeted degradation could transform therapeutics. We hypothesize MrTAC offers a novel, tissue-selective strategy to eliminate pathogenic protein aggregates. The proposal aims to establish a novel lysosomal degradation pathway using MrTAC to selectively eliminate pathogenic aggregates such as FUS, TAU, and αSYN (Aim 1), and to leverage distinct PRMTs for achieving tissue-specificity and endogenous functionality of MrTAC (Aim 2). At the completion of this work, we will have developed a novel approach for targeted protein degradation of protein aggregates, which will open an entirely novel therapeutic approach that overcomes the central limitations of current therapeutic strategies.


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 = $47,896 )
2026	2026	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/11/2026	NEW	$47,896
2026	2026	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	5/11/2026	NEW	$0
														Subtotal = $47,896

Grand Total All Awards = $47,896

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Developing innovative small-molecule lysosomal degraders for pathogenic protein aggregates in human disease

Award Number: F31NS149735

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2026

PERIOD OF PERFORMANCE END DATE: 11/30/2029

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer