Wednesday, December 24, 2025 12/24/2025

Uterine signaling networks in the pathogenesis of pulmonary lymphangioleiomyomatosis (LAM)

Award Number: R01HL153045
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/21/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Uterine signaling networks in the pathogenesis of pulmonary lymphangioleiomyomatosis (LAM) - PROJECT SUMMARY Lymphangioleiomyomatosis (LAM), a lung neoplasm affecting reproductive age women, is caused by loss-of- function mutations in tuberous sclerosis 1 (TSC1) or TSC2 genes. Hyperactivation of the mechanistic target of rapamycin 1 leads to cystic lung remodeling and progressive respiratory failure. Sirolimus therapy stabilizes lung function and improves symptoms in LAM patients, but the long-term benefit and toxicity are unknown, and some patients do not respond to therapy. LAM cells are metastatic but the primary tissue of origin is unknown. Unknown mechanisms underlying lung-specific metastasis, primary pathogenesis and female prevalence of LAM are obstacles to the development of new curative therapies. Our preliminary data from LAM lung single cell RNA sequencing (scRNAseq) analysis identified a unique population of cells (LAMCORE) expressing uterine- specific homeobox (HOX) transcription factors (TFs) that are not detected in normal lung; TF profiling of LAM patient-derived cells identified activation of Pre-B-cell leukemia homeobox 1 (PBX1), a cofactor of HOXs; comparative analysis of LAM lung scRNAseq and breast cancer cell PBX1-ChIPseq revealed overly represented LAMCORE signature genes with positive PBX1 binding peaks. Collectively, this strongly suggests a uterine origin of LAM cells and a central role of HOX/PBX1 signaling in LAM pathogenesis. The objective of this proposal is to identify mechanisms by which HOXs-associated gene networks regulate LAM pathogenesis and progression. Our central hypothesis is that HOX/PBX1 orchestrates a cell-specific gene network downstream of female hormones that regulates the survival and lung metastasis of LAMCORE cells. Three specific aims are proposed to delineate the molecular mechanisms through which HOX/PBX1 gene network contributes to LAM lesion metastasis, formation and progression. Aim 1: Determine pulmonary LAM-specific genomic and epigenomic responses and mechanisms underlying HOX/PBX1-mediated LAM pathogenesis. Aim 2: Determine the functional impacts of HOX/PBX1 network genes on metastatic potentials of LAM-derived cells in vitro and in vivo. Aim 3: Determine the effect of the HOX/PBX1 antagonist, HXR9, singly or in combination with Sirolimus, on estrogen-promoted lung metastasis potentials and lung remodeling in vivo. The completion of this proposal will provide for the first time: 1) a high-resolution integrative genomic/epigenomic blueprint of the LAMCORE cells, 2) a LAMCORE cell-specific HOX/PBX1 gene network with predicted key regulatory factors and targets within the network for follow-up perturbation and clinical diagnostic tests, 3) novel mechanistic insights into HOX/PBX1 regulatory circuits and their functional impact on LAM pathogenesis, and 4) preclinical proof-of-principle evidence for targeting HOX/PBX1-regulated female hormone-mediated LAM progression as a novel remission-inducing therapeutic strategy for LAM patients. Our work has major biomedical relevance for understanding LAM pathogenesis, developing new approaches for LAM diagnosis and designing alternative remission-inducing therapeutic strategies to maximize the benefit/toxicity ratio LAM treatment.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	4	12/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $752,914 )
2023	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	4	6/26/2023	NON-COMPETING CONTINUATION	$752,914
														Subtotal = $752,914

Issue Date FY: 2022 ( Subtotal = $761,338 )
2022	2022	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	3	6/2/2022	NON-COMPETING CONTINUATION	$761,338
														Subtotal = $761,338

Issue Date FY: 2021 ( Subtotal = $770,161 )
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	2	7/7/2021	NON-COMPETING CONTINUATION	$770,161
														Subtotal = $770,161

Issue Date FY: 2020 ( Subtotal = $790,666 )
2020	2020	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	1	7/21/2020	NEW	$790,666
														Subtotal = $790,666

Grand Total All Awards = $3,075,079

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Uterine signaling networks in the pathogenesis of pulmonary lymphangioleiomyomatosis (LAM)

Award Number: R01HL153045

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/21/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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