# Characterization of RASopathy Mutations Underlying Lymphatic Anomalies and Preparation for Clinical Development

> **NIH NIH R21** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $220,000

## Abstract

ABSTRACT
Complex lymphatic anomalies, which include a variety of diagnoses: lymphangiectasia, Central Conducting
Lymphatic Anomaly (CCLA), Generalized Lymphatic Anomaly (GLA), Kaposiform Lymphangiomatosis (KLA),
and Gorham Stout Disease (GSD), are chronically debilitating and often life-threatening diseases. Unfortunately,
for most patients, physicians can offer only palliative care that requires multiple outpatient visits and hospital
admissions. The absence of data on the molecular etiology, and lack of understanding of the underlying
molecular mechanisms in lymphatic anomalies have greatly hampered further research and precision medicine
focused clinical trials. Our long-term goal is to identify efficacious therapies for complex lymphatic anomalies.
The objective of this application is to uncover novel disease-causing genes/mutations and use in vitro and in
vivo models established in our previous studies to determine optimal treatment strategies. Our preliminary
studies have revealed multiple genes converging on the Mitogen-Activated Protein Kinase (MAPK) signaling
pathway and modeling mutations in cellular and zebrafish systems have recapitulated the essential
morphological features seen in the lymphatic anomaly patients. We have found that a handful of MEK/ERK
inhibitors showed the biochemistry and morphological reversal of the effects of mutations in RASopathy genes.
This proposal will test the hypothesis that sequencing of highly informative patients referred by an integrated
multidisciplinary lymphatic anomalies clinic will unveil novel RASopathy genes and mutations, and these can be
rapidly interrogated through our established cellular and zebrafish models to further investigate the mutation
phenotype spectrum effect and correlating molecular biomarkers. The specific aims of this proposal are to: 1)
Discover additional RASopathy genes and mutations through exome sequencing of patients with complex
lymphatic anomalies; 2) Delineate the molecular mechanisms of newly identified genes and mutations in cellular
and zebrafish models; and 3) Leverage novel disease models for therapeutic rescue to explore potential future
therapeutic targets for human disease. The results from these experiments will have a significant impact on the
field because they will answer fundamental questions regarding the genetic etiology, molecular mechanisms,
and treatment options, and most importantly, provide validated pre-clinical data for molecularly implemented
precision-based therapies for clinical trials. This knowledge will significantly advance our understanding of
different types of lymphatic anomalies.

## Key facts

- **NIH application ID:** 10215641
- **Project number:** 5R21TR003331-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Dong Li
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $220,000
- **Award type:** 5
- **Project period:** 2020-07-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10215641

## Citation

> US National Institutes of Health, RePORTER application 10215641, Characterization of RASopathy Mutations Underlying Lymphatic Anomalies and Preparation for Clinical Development (5R21TR003331-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10215641. Licensed CC0.

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