# Epigenetic regulation of lymphatic development

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $609,668

## Abstract

PROJECT SUMMARY / ABSTRACT:
Congenital or neonatal accumulation of chyle in the pleural space is the most common cause of pleural effusion
affecting 1 in 10,000 births with mortality rates between 20-60%. Neonatal patients with a spontaneous
accumulation of chyle frequently exhibit bilateral pleural effusion, severe respiratory distress, tachypnea, and
cyanosis, suggesting the mechanical effect of compression on lung compliance and impairment of gas exchange
in alveoli. Although Dr. Bartloet established accumulation of chyle in the pleural space as a lymphatic anomaly
in 1633, the mechanism for their formation and treatment have not been fully defined. Recent studies reveal the
requirement of prenatal lymphatic function to drain pleural fluid and promote the inflation of lungs at birth, which
is required for viability. To accomplish this, an extensive network of lymphatic vessels within the pleura, the
intercostal space, the perivascular spaces of arterioles and venules, and the connective tissue of the terminal
and respiratory bronchioles maintain fluid homeostasis and promote effective gas exchange. Abnormal dilation
of these lymphatic vessels, known as lymphangiectasia, is frequently associated with neonatal chylous effusion,
immature lungs, and severe respiratory distress with mortality. Even though Dr. Rudolf Virchow described
neonatal pulmonary lymphangiectasia as early as 1856, the underlying causal etiology and treatment options
remain elusive. Our preliminary studies identify an unexpected causal link between pathological MAPK activation
and lymphangiectasia in mice and humans. Pathological activation of lymphatic MAPK causes severe pulmonary
lymphangiectasia, accumulation of chyle in the pleural space, and complete lethality. Preliminary analyses of
human pathological tissue samples from patients diagnosed with lymphangiectasia revealed sustained MAPK
activation within lymphatic endothelial cells and recapitulated the murine phenotype. Mechanistically, the
genome-wide phosphorylated MAPK occupancy screen revealed direct regulation of an evolutionarily conserved
genetic program required for lymphatic vessel structure and function. This research program aims to identify how
the MAPK signaling pathway establishes and maintains a specific transcriptional program for lymphatic vessel
development. In addition, proposed studies will identify the mechanisms by which specific kinases and
transcription factors interact to regulate the chromatin recruitment of MAPK within developing pulmonary
lymphatic vasculature. The set of proposed studies has broad significance for understanding how signaling
pathways intersect with chromatin-modifying transcription factors to regulate the development of organ-specific
lymphatic vasculature and could be highly applicable to the entire field of congenital vascular diseases.

## Key facts

- **NIH application ID:** 10540097
- **Project number:** 2R01HL141377-05
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Chinmay M Trivedi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $609,668
- **Award type:** 2
- **Project period:** 2018-05-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10540097

## Citation

> US National Institutes of Health, RePORTER application 10540097, Epigenetic regulation of lymphatic development (2R01HL141377-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10540097. Licensed CC0.

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