# Advancing Proteomics Technologies to Decipher the Ubiquitin-Proteasome System

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA-IRVINE · 2023 · $225,854

## Abstract

Alzheimer’s disease (AD) is an incurable age-related progressive neurodegenerative disorder. Currently,
molecular mechanisms underlying memory loss and cognitive defects caused by AD remain elusive. Systematic
characterization of the central nervous system (CNS) is essential to understanding neurodegenerative disorders.
However, detailed analysis of neuronal networks remains extremely challenging due to the enormous complexity
of the human brain, which is comprised of nearly a hundred billion neurons that interconnect to form an
exceedingly intricate and delicate neuronal circuitry. While current MS-based proteomics approaches have
enabled global profiling of proteomes and posttranslational modifications in human brains, our understanding of
the dynamic and functional organization and regulation of neuronal networks associated with AD remains very
limited. Therefore, there is an urgent need to define the molecular networks associated with AD to advance our
understanding of its pathobiology. Protein-protein interactions (PPIs) are fundamental to the formation of protein
complexes and crucial for orchestrating a diverse array of pathways in regulating cellular activities. Aberrant
PPIs have been associated with AD and other neurodegenerative disorders, however, molecular alterations in
protein complexes and network pathways specific to AD development have not been well explored. Therefore,
systems-wide profiling of interaction landscapes of protein complexes in healthy and diseased states is crucial
for a deeper understanding of neurobiology and neuropathology, and ultimately the discovery of novel
interaction-based diagnostics and therapeutics. In this supplement, we propose to employ cross-linking mass
spectrometry (XL-MS) technologies to dissect protein interaction landscapes in brain tissues of AD models and
patient samples to allow us to unravel neuronal networks with PPI identities and contact sites for the first time.
The molecular details determined by our novel XL-MS technology will undoubtedly provide unique insights that
cannot be easily revealed by other approaches. The results will allow us to define protein modules and networks
associated with AD and thus uncover new molecular details underlying the pathophysiological mechanisms of
AD.

## Key facts

- **NIH application ID:** 10713531
- **Project number:** 3R35GM145249-02S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Lan Huang
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $225,854
- **Award type:** 3
- **Project period:** 2022-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10713531

## Citation

> US National Institutes of Health, RePORTER application 10713531, Advancing Proteomics Technologies to Decipher the Ubiquitin-Proteasome System (3R35GM145249-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10713531. Licensed CC0.

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