# Development of Imaging Probes for Risk Assessment of Alzheimer's Disease using  Phage Display

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $345,854

## Abstract

Project Summary
Parent Grant Summary:
Proteases represent one of the largest and most well characterized families of enzymes in the human genome.
Furthermore, there are many human health conditions such as cancer that are associated with alterations in
protease activity and function. Therefore, specific molecular probes that allow individual protease activities to
be imaged during disease progression in vivo would both be transformative in our understanding of the roles of
proteolytic events that contribute to disease pathology while also providing a direct methods for early disease
monitoring and response to therapy. The past decade has produced many diverse classes of molecular probes
that can be used for imaging applications. Perhaps one of the most powerful of these reagents is the activity-
based probe (ABP). However, the broad application of ABPs is typically limited by the need to painstakingly
optimize probes using synthetic chemistry and often probes lack absolute specificity for a given target enzyme.
This proposal will focus on establishing an innovative technology that will allow rapid design of ABPs with
exceptional specificity for any given protease target of interest. This will involve application of a phage display
method to screen diverse libraries of chemically constrained bi-cyclic peptides linked to a protease reactive
electrophile to iteratively screen for covalent binding elements with high potency and selectivity. We propose to
establish and validate the phage screening method using two stromal-cell derived protease targets, cathepsin
S (cat S) and fibroblast activation protein (FAP), involved in key aspects of tumorigenesis. These new probes
will then be validated for imaging applications in mouse models of cancer. The technology developed in this
proposal will result in not only a new general method for protease ABP development but also will produce
probes with potential future clinical applications in cancer imaging.
Supplement Project Summary:
Alzheimer’s Disease (AD) is a progressive neurodegenerative disease characterized by inflammation and cell
death in the brain that leads to loss of cognitive function. Although a number of genetic links have been
established and many cellular events associated with disease pathology have been established, very little is
known about key risk factors and non-genetic triggers of this debilitating disease. Recent findings that one of
the primary proteins linked to AD pathogenesis, b-amyloid, can function as an anti-microbial peptide motivated
studies to identify a role for an infectious agent as a possible cause for the disease. To this end, a number of
recent efforts have identified the presence of the pathogenic bacteria, Porphyromonas gingivalis, in greater
than 90% of postmortem brains of patients with AD. This pathogen is typically found in the mouth where it is
involved in the progression of chronic periodontitis (CP) but can also be found in other locations within the
body incl...

## Key facts

- **NIH application ID:** 10287384
- **Project number:** 3R01EB026285-04S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Matthew Bogyo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $345,854
- **Award type:** 3
- **Project period:** 2018-05-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10287384

## Citation

> US National Institutes of Health, RePORTER application 10287384, Development of Imaging Probes for Risk Assessment of Alzheimer's Disease using  Phage Display (3R01EB026285-04S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10287384. Licensed CC0.

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