# TSC Proteins in the Lymphatic Vasculature

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2024 · $682,235

## Abstract

Tuberous Sclerosis Complex (TSC) is a chronic disease that is caused by mutations in the genes TSC1 or TSC2.
The disease affects 2 million people worldwide and there is no cure for TSC disease. Symptoms include
formation of large tumors called hamartomas in various organs of the body, including the brain, the kidney, and
the lung. One of the severe complications associated with these tumors is chylothorax, which is the accumulation
of chyle in the space between the pleura and chest cavity. Chyle is a milky fluid that originates from lymphatic
vessels draining dietary fats. Chylothorax can cause difficulty breathing, tachypnea, chest pain, respiratory
failure, and death. Although chylothorax indicates malfunctioning lymphatic vessels in TSC patients, the current
dogma is that tumors compress/obstruct the lymphatic vessels near the lung resulting in leakage, and it remains
unknown whether TSC mutations in lymphatic endothelial cells are a causative factor of chylothorax. Thus, a
significant unmet need is to determine whether lymphatic vessels are involved in TSC disease and delineate the
pathological changes of the lymphatic vasculature due to TSC loss-of-function, which will identify new signaling
pathways and molecular targets for this disease. Our preliminary data show that lymphatic-specific deletion of
the Tsc genes in mice leads to chylothorax and is accompanied by a severe loss of lymphatic valves. These data
suggest that the lymphatic vasculature is involved in TSC disease and regressing lymphatic valves allow lymph
to flow backwards into the paravertebral and intercostal lymphatic capillaries, which causes lymph leakage from
the thoracic duct into the chest cavity. Aim 1 will determine pathological changes in the lymphatic vasculature
upon genetic deletion of Tsc genes, Aim 2 will identify the molecular mechanisms by which loss of Tsc1 or Tsc2
causes the loss of lymphatic valves, and Aim 3 will investigate novel approach to reverse lymphatic valve loss
in the Tsc knockouts. It is highly anticipated that these aims will identify new pathogenic features of TSC disease
and new signaling pathways affected by loss of TSC signaling.

## Key facts

- **NIH application ID:** 10841591
- **Project number:** 5R01HL166981-02
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Ying Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $682,235
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841591

## Citation

> US National Institutes of Health, RePORTER application 10841591, TSC Proteins in the Lymphatic Vasculature (5R01HL166981-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10841591. Licensed CC0.

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