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Chronic Lung Allograft Dysfunction: Role for Tumor Suppressor LKB1 in Exosomes

Award Number: R01HL156891
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Chronic Lung Allograft Dysfunction: Role for Tumor Suppressor LKB1 in Exosomes - Project Summary/Abstract Lung transplantation (LTx) is a therapeutic option for patients with advanced lung diseases. Long‐term survival after LTx is, however, limited by chronic lung allograft dysfunction (CLAD). CLAD most commonly manifests itself as bronchiolitis obliterans syndrome (BOS) and about 50% of recipients (LTxRs) will develop BOS within 5 years post-LTx. Epithelial-mesenchymal-transition (EMT) and fibrosis have been implicated in the pathogenesis of BOS. We demonstrated that liver kinase 1 (LKB1), a tumor suppressor gene, is downregulated in BOS but not in stable biopsies using both western blotting and aldehyde bead conjugated exosomes by flow cytometry. We also demonstrated that LKB1 knockdown induces exosome release from airway epithelial cell line, BEAS-2B, and another human airway epithelial cell line, HPBEC. Exosomes released from LTxRs with BOS also induces EMT which was regulated by LKB1 in BEAS-2B and HPBEC. NanoString analyses identified LKB1 knockdown induced PDGFRβ expression in human airway epithelial cells. We also demonstrated that biopsies from BOS LTxRs had reduced LKB1 and increased PDGFβR with inverse correlation. These novel findings indicate an important role for the tumor suppressor gene LKB1 in the regulation of PDGFβR and, therefore, fibrosis development. Studies proposed using both clinical samples and in vitro cell culture model, we will define the mechanism by which exosomes with downregulated LKB1 released from transplanted lungs mediate EMT leading to CLAD. Aim 1 of the proposal is to determine serially whether inactivation of LKB1 in exosomes isolated from plasma from LTxRs with known risk factors (primary graft dysfunction [PGD]), acute rejection [AR] and respiratory viral infections [RVI]) can be useful as a non- invasive biomarker for LTxRs at risk for CLAD. Our hypothesis is that persistent downregulation of LKB1 in exosomes will be a biomarker for LTxRs at risk for developing CLAD. The second goal is to determine and quantitate exosomes with LKB1/AMPK1 using serial retrospectively stored plasma from LTxRs with known clinical diagnosis will be a more sensitive marker for CLAD and to determine its potential to differentiate restrictive allograft syndrome and BOS by defining their immunological and molecular properties. Our third goal is to define the mechanisms by which loss of LKB1 results in EMT and upregulation of PDGFRβ and promotes the pathogenesis of CLAD. Towards this; a) we will define the regulatory mechanisms suppressing LKB1 in LTxRs with PGD, AR and RVI, risk factors for CLAD, and b) we will determine the mechanisms by which LKB1 downregulation leads to upregulation of PDGFRβ and its signaling pathways which contributes towards development of fibrosis. Results from these studies will provide novel information for the role of LKB1, in EMT and fibrosis related pathologies including CLAD following LTx.


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: 2025 ( Subtotal = $417,885 )
2025	2025	DIGNITY HEALTH	185 BERRY ST STE 200	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Lung Diseases Research	000	4	7/16/2025	NON-COMPETING CONTINUATION	$417,885
														Subtotal = $417,885

Issue Date FY: 2024 ( Subtotal = $414,150 )
2024	2024	DIGNITY HEALTH	185 BERRY ST STE 200	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Lung Diseases Research	000	3	6/10/2024	NON-COMPETING CONTINUATION	$414,150
														Subtotal = $414,150

Issue Date FY: 2023 ( Subtotal = $410,524 )
2023	2023	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Lung Diseases Research	000	2	6/23/2023	NON-COMPETING CONTINUATION	$410,524
														Subtotal = $410,524

Issue Date FY: 2022 ( Subtotal = $407,004 )
2022	2022	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Lung Diseases Research	000	1	6/13/2022	NEW	$407,004
														Subtotal = $407,004

Grand Total All Awards = $1,649,563

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Chronic Lung Allograft Dysfunction: Role for Tumor Suppressor LKB1 in Exosomes

Award Number: R01HL156891

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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