# The Molecular and Genetic Pathogenesis of LAM

> **NIH NIH U01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $877,667

## Abstract

Abstract
 Lymphangioleiomyomatosis (LAM) is a progressive multi-system disease of women characterized by
cystic lung destruction, renal angiomyolipomas, and chylous pleural effusions. Lymphangiogenesis is prominent
in pulmonary LAM nodules and serum VEGF-D levels above 800 pg/ml are a diagnostic biomarker of LAM. The
majority of LAM cells carry bi-allelic inactivating mutations in the tuberous sclerosis complex (TSC) genes and
circulating LAM cells with TSC2 loss of heterozygosity can be detected in the blood.
 The TSC protein complex inhibits the mammalian/mechanistic target of rapamycin (mTORC1) via the
small GTPase Rheb. mTORC1 acts as a molecular sensor that regulates cell growth, metabolism, autophagy,
and microRNA biogenesis. Pivotal clinical trials have demonstrated clinical benefit from treatment with sirolimus
(Rapamycin) or its analogs (Rapalogs) in LAM and TSC. Collectively these data indicate that Rapamycin is an
effective suppressive therapy for LAM. However, lung function decline resumes, and tumors regrow when the
drug is discontinued. Therefore, therapy must be used chronically – perhaps lifelong. This highlights the urgent
unmet need for novel therapeutic strategies in LAM and TSC to eliminate (rather than suppress) LAM cells, for
novel biomarkers allowing personalization of therapy and to better understand genetic and clinical factors that
may help to predict the severity of LAM.
 This UO1 brings together a unique team of leaders in lymphangioleiomyomatosis (LAM) and tuberous
sclerosis complex (TSC) to address key unanswered questions with high clinical impact. First, identifying novel
biomarkers of LAM. Using in vitro and in vivo models of LAM and single cell RNA sequencing from human LAM
lungs, systematic analysis of the LAM cell “secretome” will elucidate the pathogenesis of LAM revealing novel
prognostic biomarkers. Second, investigating novel mTORC1-independent pathways leading to LAM cell
survival that could be therapeutically targeted to induce LAM cell death. Third, analysis of genetic modifiers of
LAM and of potential cryptic generalized somatic mosaicism for TSC2 gene mutations to elucidate LAM
pathogenesis and help identify patients at highest risk of progression.

## Key facts

- **NIH application ID:** 9914735
- **Project number:** 2U01HL131022-04
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Souheil El-Chemaly
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $877,667
- **Award type:** 2
- **Project period:** 2016-09-21 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9914735

## Citation

> US National Institutes of Health, RePORTER application 9914735, The Molecular and Genetic Pathogenesis of LAM (2U01HL131022-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9914735. Licensed CC0.

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