# Enabling Top-Down Proteomics through Material Chemistry and Nanotechnology

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $298,280

## Abstract

Summary
 In the post-genomics era, a comprehensive analysis of “proteoforms” that arise from genetic variations and
post-translational modifications (PTMs) is essential for understanding biological systems at a functional level and
for dissecting complex molecular systems with consideration of individual variability for precision medicine. Top-
down mass spectrometry (MS)-based proteomics that analyzes intact proteins is the most powerful method to
comprehensively characterize proteoforms to decipher the PTM codes together with sequence variations.
Although significant strides have been made recently in both MS hardware and software to advance top-down
MS closer to the mainstream, top-down proteomics still faces major challenges. In particular, the proteome is
extremely complex and has a high dynamic range in addition to the low solubility of many proteins, making it
highly challenging for high-throughput proteomic study. Building on the success in the last funding period, in this
multiple-PI renewal application, we will continue to develop innovative strategies empowered by nanotechnology
and materials/organic chemistry to further address the challenges in top-down proteomics. The specific
objectives of this proposal are: 1) To address the protein solubility challenge, we will develop a novel strategy
enabled by a photocleavable surfactant for extracellular matrix (ECM) proteomics; and design, synthesize, and
evaluate a novel class of photocleavable nonionic surfactants that can retain the native structures of proteins for
native MS-based top-down proteomics. 2) To address the high dynamic range challenge, we will develop novel
surface functionalized magnetic nanoparticles (NPs) to mimic antibodies for capturing and enriching low
abundance proteins, such as cardiac troponin I (cTnI, a gold-standard biomarker for heart diseases) from
tissues/blood and G-protein coupled receptors (GPCRs, a major class of drug targets) from cells/tissues, for
downstream comprehensive analysis of all proteoforms by top-down proteomics. Our highly interdisciplinary
approach integrates materials chemistry/nanotechnology with top-down MS-based proteomics, and is based on
an existing productive collaboration between two PIs that has led to significant progress and publications from
the past funding period. Success in our proposed research will provide innovative tools to enable top-down
proteomics of poorly soluble and low abundance proteins, which will lay important technological foundation for
understanding the critical role that ECM plays in disease progression in cancer and cardiac diseases, defining
the structure-function relationship of native membrane complexes, developing a comprehensive cTnI assay for
the diagnosis of cardiac diseases with high accuracy, and understanding the important roles of GPCR signaling
during the onset of numerous human diseases including cancer, diabetes, and cardiovascular diseases.

## Key facts

- **NIH application ID:** 10246801
- **Project number:** 5R01GM117058-06
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Ying Ge
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $298,280
- **Award type:** 5
- **Project period:** 2015-09-25 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246801

## Citation

> US National Institutes of Health, RePORTER application 10246801, Enabling Top-Down Proteomics through Material Chemistry and Nanotechnology (5R01GM117058-06). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10246801. Licensed CC0.

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