# Characterizing the Formation and Function of Bone Lymphatics

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $404,328

## Abstract

PROJECT SUMMARY
Gorham-Stout disease (GSD) and generalized lymphatic anomaly (GLA) are related diseases of the lymphatic
system. GSD and GLA patients develop ectopic lymphatics in bone and gradually lose bone. Unfortunately, our
understanding of the biology of GLA and GSD has not significantly advanced over the past 60 years. This gap
in knowledge has made it difficult to treat GLA and GSD patients. Our long-term goal is to identify effective
therapies and biomarkers for GLA and GSD. The objective of this application, which is the first step in pursuit of
that goal, is to use novel mouse models developed in my laboratory to determine how lymphatic vessels form in
bone and promote bone loss. PIK3CA encodes the catalytic subunit of phosphatidylinositol 3-kinase (PI3K). Our
preliminary studies have revealed that mice that express an active form of PIK3CA (PIK3CALEC) in their lymphatic
endothelial cells (LECs) develop irregular lymphatics in their soft tissues and bones. VEGF-C is a growth factor
that stimulates PI3K signaling in LECs by activating VEGFR3. To induce excessive PI3K signaling specifically
in LECs around bone, we created transgenic mice that overexpress VEGF-C in bone (VegfcOE). We have found
that overexpression of VEGF-C in bone causes lymphatics to form in bone and bone loss. We have also found
that rapamycin (FDA-approved mTOR inhibitor) inhibits lymphangiogenesis in PIK3CALEC mice and VegfcOE
mice. This proposal will test the hypothesis that excessive PI3K/mTOR signaling in LECs stimulates the formation
of lymphatic vessels in bone and osteoclast-mediated bone resorption. The specific aims of this proposal are to:
1) Characterize the development of bone lymphatics in PIK3CALEC and VegfcOE mice; 2) Determine the
mechanism of bone loss in PIK3CALEC and VegfcOE mice; and 3) Determine the effect of rapamycin on
lymphangiogenesis and osteolysis in PIK3CALEC and VegfcOE mice. The results from these experiments will have
a significant impact on the field because they will answer fundamental questions regarding the biology of bone
lymphatics. Our experiments will reveal how lymphatics form in bone and promote bone loss. This knowledge
will significantly advance our understanding of processes that are relevant to the pathogenesis of GLA and GSD
and could be used to inhibit lymphangiogenesis in GLA, GSD, and other human diseases.

## Key facts

- **NIH application ID:** 9849310
- **Project number:** 5R01HL144793-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Michael Thomas Dellinger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $404,328
- **Award type:** 5
- **Project period:** 2019-01-10 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849310

## Citation

> US National Institutes of Health, RePORTER application 9849310, Characterizing the Formation and Function of Bone Lymphatics (5R01HL144793-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9849310. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*