# Protein Amyloid Formation and Inhibition Studied by Mass Spectrometry

> **NIH NIH R35** · UNIVERSITY OF MASSACHUSETTS AMHERST · 2022 · $398,750

## Abstract

Project Summary
 Several human proteins are known to form amyloid fibrils, and these fibrils are associated
with devastating diseases, including Alzheimer's, Parkinson's, type II diabetes, and dialysis-
related amyloidosis (DRA). The protein β-2-microglobulin (β2m) forms amyloid fibrils in the joints
of patients undergoing hemodialysis, leading to DRA. While protein amyloid formation has been
extensively studied, molecular-level information about the early stages of amyloid formation is
only beginning to be revealed for a few proteins. This information, though, is critical for the rational
development of therapeutics against amyloid diseases, particularly for DRA that has no treatment.
 Our group has been developing and applying new mass spectrometry (MS) methods to reveal
structural and oligomeric changes that β2m undergoes before forming amyloid fibrils. Such
structural information is very challenging to obtain using traditional biophysical methods, and the
structural insight from our new methods has led to exciting discoveries about the first steps of
protein amyloid formation. We are beginning to utilize this insight to find inhibitors of DRA.
 The research in this MIRA project seeks to (i) develop new methods that will deepen our
mechanistic insight into the first steps of β2m amyloid formation and (ii) leverage this new
mechanistic information to discover robust inhibitors of β2m amyloid formation. These goals will
be accomplished by creating new MS methods that rely on covalent labeling, ion mobility, and
computational modeling. These new approaches will allow us to probe the energy landscape of
the structural switch that initiates β2m amyloid formation, providing unprecedented quantitative
insight into the factors that cause this normally stable protein to become amyloidogenic. We will
also explore new methods to characterize the on- and off-pathway isomeric oligomers that are
present during the early stages of β2m amyloid formation, allowing us to reveal the specific
protein-protein interactions that lead to amyloids. Altogether, the structural insights that we obtain
will then be utilized to discover new inhibitors of β2m amyloid formation. Specific outcomes of this
research will be new biophysical tools to study protein amyloid formation and the identification of
inhibitors that could lead to therapeutics against DRA. The universality of the techniques
developed in this work will also make them applicable to other amyloid systems and diseases.

## Key facts

- **NIH application ID:** 10406483
- **Project number:** 1R35GM145272-01
- **Recipient organization:** UNIVERSITY OF MASSACHUSETTS AMHERST
- **Principal Investigator:** RICHARD W VACHET
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $398,750
- **Award type:** 1
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10406483

## Citation

> US National Institutes of Health, RePORTER application 10406483, Protein Amyloid Formation and Inhibition Studied by Mass Spectrometry (1R35GM145272-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10406483. Licensed CC0.

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