# Rejuvenating Skeletal Health Through A Novel Brain-Bone Axis

> **NIH NIH U01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $515,861

## Abstract

Project Summary/Abstract
Interorgan communication between the brain and peripheral tissues maintains a range of homeostatic
responses. Efforts to identify new facets of interorgan crosstalk remain sparse. Missed opportunities exist
because of the siloed nature of physiological research, especially between the brain and body. Cracking the
molecular code in the brain-body dialog is also technically challenging and requires time-consuming,
interdisciplinary preclinical in vivo studies. We previously discovered that eliminating ERa in a subset of
hypothalamic neurons leads to a massive increase in trabecular bone mass and strength that persists with aging
in female mice. Our focus on a brain-bone interaction that influences bone mass and bone fat underscores
the potential role of select neurons to significantly alter peripheral tissues. Here, we will ask how this brain-
derived factor increases bone mass while permanently decreasing bone fat, two opposing features of skeletal
aging.
In new data, we find that the high bone mass in our mutant mouse model system results from humoral rather
than neuronal cues. An essential first step toward translating this work will be to identify this circulatory anabolic
bone factor. While this goal is simple in principle, it is extremely difficult to achieve. We were fortunate to discover
that this high bone mass phenotype reverses with a dietary challenge. High-resolution genomic approaches then
allowed us to identify and test the most promising candidates through gain-of-function and loss-of-function
approaches. Using in vitro, ex-vivo, and in vivo model systems, we provide the first molecular and cellular insights
into how the brain influences bone mass, bone fat, and skeletal stem cell function. We will elucidate how and
why this brain-derived anabolic bone factor increases bone formation.
Our team brings together expertise in neuroendocrinology, bone and skeletal stem cell biology, and the clinical
practice of treating metabolic and bone disorders. We are using state-of-the-art methods to pursue hypothesis-
driven questions aimed at decoding a powerful dialog between the brain and bone. Eventually, we wish to
translate these preclinical studies to skeletal and metabolic disorders that are associated with or accelerated in
human aging. Our research program fits squarely within this new NIA mandate to transform our understanding
of interorgan interactions and advance strategies for improving age-related decline in skeletal health, especially
in women.

## Key facts

- **NIH application ID:** 10852596
- **Project number:** 1U01AG086165-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** HOLLY A. INGRAHAM
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $515,861
- **Award type:** 1
- **Project period:** 2024-06-15 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10852596

## Citation

> US National Institutes of Health, RePORTER application 10852596, Rejuvenating Skeletal Health Through A Novel Brain-Bone Axis (1U01AG086165-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10852596. Licensed CC0.

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