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Investigate the role of extracellular vesicles in promoting the progression of pulmonary lymphangioleiomyomatosis

Award Number: R01HL160972
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/20/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Investigate the role of extracellular vesicles in promoting the progression of pulmonary lymphangioleiomyomatosis - Project Summary. Pulmonary lymphangioleiomyomatosis (LAM) is metastatic, understudied sarcoma, which predominantly affects women, and manifests as proliferation of tumor smooth muscle-like cells within the lungs. LAM is caused by TSC1/2 loss of function mutations that lead to mTOR hyperactivation, therefore, mTOR inhibitor rapamycin is approved for LAM. However, although rapamycin stabilizes the lung function, after therapy cessation the progressive decline in the lung function resumes leading to respiratory insufficiency and there are no other drugs approved for LAM. Thus, the discovery of new therapeutic targets for LAM is critically needed. The objectives of this project are: (1) determine a role of extracellular vesicles (EV) in LAM metastasis and (2) provide the proof-of-concept for targeting EV for LAM. A role of EV in LAM has not yet been explored, however, our published and preliminary studies indicate that (a) EV cargo contribute to LAM metastasis via enhancing cancer stem-cell (CSC) characteristics and survival of circulating LAM cells and lung remodeling and (b) rapamycin affects EV, possibly, leading to enhanced seeding of the lungs by LAM cells. These data lead to our central hypothesis that TSC1/2-null-cell-derived EV cargo, containing SOX-10, integrins, and c-Src, increases LAM metastasis via increasing CSC plasticity and survival of circulating LAM cells and via lung extracellular matrix (ECM) remodeling mediated by resident lung fibroblasts, which enhances lung seeding by LAM cells. Rapamycin enhances EV production by TSC1/2-null cells and their quality, which may explain faster clearance of LAM cells from the circulation of patients treated with rapamycin analogs but simultaneously and adversely enhances LAM lung metastasis. A key translational corollary of this hypothesis is that LAM will be sensitive to inhibition of the EV pathway and targeting EV may improve outcomes in rapamycin treated patients. To test this hypothesis we will determine: Aim 1. The effect of EV-cargo on CSC plasticity and survival of LAM cells; Aim 2. Impact of EV-cargo on lung remodeling and lung seeding by LAM cells; and Aim 3. The effect of inhibitors of EV uptake or EV biogenesis, individually or in combination with rapamycin, on lung remodeling and LAM metastasis in vivo. Our approaches include: the culture systems to test impact of EV-cargo on circulating LAM cells, novel LAM mouse models in conjunction with longitudinal non-invasive live imaging, and studies with patient samples to corroborate in vitro and mouse data and establish EV cargo as biomarker of LAM progression. This project will impact the filed by establishing EV is a new therapeutic target for LAM and providing foundation for repurposing approved EV-targeting drugs for LAM.


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	2025	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH ST	LUBBOCK	TX	79430	LUBBOCK	USA	Lung Diseases Research	000	4	10/21/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $687,328 )
2025	2025	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH ST	LUBBOCK	TX	79430	LUBBOCK	USA	Lung Diseases Research	000	4	11/26/2024	NON-COMPETING CONTINUATION	$618,596
2025	2025	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH ST	LUBBOCK	TX	79430	LUBBOCK	USA	Lung Diseases Research	001	4	8/20/2025	NON-COMPETING CONTINUATION	$68,732
														Subtotal = $687,328

Issue Date FY: 2024 ( Subtotal = $679,938 )
2024	2024	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH ST	LUBBOCK	TX	79430	LUBBOCK	USA	Lung Diseases Research	001	3	6/24/2024	NON-COMPETING CONTINUATION	$55,505
2024	2024	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Lung Diseases Research	000	3	1/12/2024	NON-COMPETING CONTINUATION	$624,433
														Subtotal = $679,938

Issue Date FY: 2023 ( Subtotal = $699,460 )
2023	2023	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Lung Diseases Research	000	2	11/23/2022	NON-COMPETING CONTINUATION	$629,514
2023	2023	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Lung Diseases Research	001	2	3/6/2023	NON-COMPETING CONTINUATION	$69,946
														Subtotal = $699,460

Issue Date FY: 2022 ( Subtotal = $718,036 )
2022	2022	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Lung Diseases Research	000	1	12/13/2021	NEW	$718,036
														Subtotal = $718,036

Grand Total All Awards = $2,784,762

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Investigate the role of extracellular vesicles in promoting the progression of pulmonary lymphangioleiomyomatosis

Award Number: R01HL160972

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/20/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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