# Deciphering Mechanisms of Nitrogen-Containing Bisphosphonates

> **NIH NIH R00** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $232,028

## Abstract

Project Summary/Abstract
Osteoporosis and low bone mass (osteopenia) are estimated to affect 55 percent of the American population
over the age of 50; over 50 million people in total, with major consequences for the patients' quality of life. The
current standard treatment for osteoporosis is administration of nitrogen-containing bisphosphonates (NBPs).
However, the mechanism by which these highly-charged drugs enter, traffic through, and reach their molecular
targets and effect target cells is poorly understood. The long-term goal of this proposal is to deconstruct the
molecular pathways essential for NBP response. To do this, I will build upon preliminary genetic studies by
using cell assays and mouse models, as well as in vitro binding and functional assays to explore the
interactions between NBPs and my identified targets. Our previous work utilized two distinct high-throughput
genome-wide screens to identify over 200 genes required for the action of NBPs. In two recent manuscripts, I
have initially focused on the role of two genes, ATRAID and SLC37A3, that strongly affect the response to
NBPs, and found them likely to be required for the endocytic trafficking of these drugs. This proposal builds
upon this preliminary work to i) characterize the physiological role of ATRAID and SLC37A3 in the organismal
response to NBPs, ii) further examine their basal molecular function and how they facilitate NBP trafficking,
and iii) investigate the role of two transcription factors, associated by GWAS with changes in BMD, that when
depleted may sensitize cells to the effects of NBPs. Together, these studies generate a broader picture of the
molecular pathways that NBP uses to affect cells by investigating other genes identified in our initial screens.
While this proposal by necessity focuses on a subset of identified genes, I envision it will set the stage for my
future work determining how genes identified in our screens may predict patient response to NBPs, including
efficacy of treatment, dosage of NBPs needed, and adverse side effects. Moreover, this focus on
understanding the mechanisms of an inexpensive, commonly prescribed drug will bring new perspectives and
hypotheses to the development of treatment strategies for osteoporosis.
During the early stage of this award, I will gain valuable technical skills, including in analysis of mouse models
of osteoporosis, culture of primary bone cells, and biochemistry of protein interactions, as well as a deeper
training and immersion in bone and endocrine biology, that will altogether enable me to develop a unique
research program, which I intend to establish at a hospital-based research institute. Under the mentoring of my
formal advisory committee, I will develop important soft skills, such as presentation skills, lab leadership, and
grant writing. This combination of training, support and career mentoring will be instrumental in my transition to
independence as a tenure-track faculty member.

## Key facts

- **NIH application ID:** 10764198
- **Project number:** 5R00AR073903-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Lauren Elizabeth Surface
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $232,028
- **Award type:** 5
- **Project period:** 2022-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764198

## Citation

> US National Institutes of Health, RePORTER application 10764198, Deciphering Mechanisms of Nitrogen-Containing Bisphosphonates (5R00AR073903-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10764198. Licensed CC0.

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