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Novel exosomal niches for alveolar stem cell-bassed repair of ARDS

Award Number: R01HL134828
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2017
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Novel exosomal niches for alveolar stem cell-bassed repair of ARDS - Summary. The regulation of alveolar regeneration of injured lungs by exosomal signals in acute respiratory distress syndrome (ARDS) are incompletely studied. We have identified exosomal proteins in bronchoalveolar lavage fluid (BALF) of ARDS patients that are closely association with the severity of lung injury. In ARDS, clinical severity is graded by the ratio of arterial oxygen tension (PaO2 in mmHg) to the fraction of inspired oxygen (FiO2). We have identified stem cell-related niche proteins that are present in mild (200£PaO2/FiO2<300 mmHg) to moderate ARDS (100£PaO2/FiO2<200 mmHg) but reduced in severe ARDS (PaO2/FiO2<100 mmHg). A key pathological process in ARDS is damage to the alveolar epithelium, which has been demonstrated in numerous preclinical and clinical studies to be associated with ARDS severity. Therefore, we hypothesize that exosomal signals for lung stem cell-mediated re-alveolarization are determinants of ARDS outcomes. Several findings support this hypothesis. 1) Exosomes are effective autocrine/paracrine pathways for stem cell lineage in injured organs. 2) Exosomal proteins are protected from catalysis by enzymes in inflamed tissues. 3) Unbiased high throughput proteomic analysis and advanced bioinformatic platforms have successfully identified novel biomarkers for other diseases. 4) Although the etiologies of ARDS are diverse, the repair processes mediated by epithelial stem/progenitor cells regulated by niches seem to be similar based on preclinical studies. Our objective is to test this hypothesis with BALF samples and patients' clinical data from NIH/NHLBI-supported clinical trials, prioritize niche molecules, and validate the results in genetically bioengineered mice and organoids of alveolar type 2 (AT2) epithelial cells. We will apply novel “exosomics” approaches, cutting-edge bioinformatics, three-dimensional culture models, robust cell origin tracking, and supervised machine learning algorithms. There are three specific aims: Aim 1 is designed to identify exosomal signaling pathways and networks in lavage that regulate the lineage of lung stem cells for re-alveolarization. We hypothesize that stem cell-mediated re- alveolarization has been suppressed in severe ARDS patients due to the disruption of key exosomal niches. We will prioritize differentially expressed exosomal proteins and related signaling pathways and networks using R packages. Aim 2 is designed to detect and optimize regenerative predictors for re-alveolarization of injured lungs. We hypothesize that the significantly differential exosomal molecules in lavage will be associated with clinical data in ARDS patients. We will perform unbiased clustering and supervised machine learning algorithms to develop models for discovering critical signals for lung regeneration. The prioritized exosomal predictors will be compared with traditional whole-protein markers for accuracy and applicability. Aim 3 will validate selected exosomal signals for AT2-mediated re-alveolarization. We will confirm that the exosomal molecules regulate the lineage of human and mouse AT2 cells in 3D organoids and mice. These studies will identify stem cell-specific exosomal molecules as potential pharmaceutic targets for ARDS.


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 = $414,374 )
2025	2025	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Lung Diseases Research	000	8	4/4/2025	NON-COMPETING CONTINUATION	$414,374
														Subtotal = $414,374

Issue Date FY: 2024 ( Subtotal = $457,366 )
2024	2024	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Lung Diseases Research	002	7	4/16/2024	NON-COMPETING CONTINUATION	$420,029
2024	2024	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Lung Diseases Research	003	7	6/25/2024	NON-COMPETING CONTINUATION	$37,337
2024	2023	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Lung Diseases Research	001	6	11/21/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$200,386
2024	2022	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER	11937 US HIGHWAY 271	TYLER	TX	75708	SMITH	USA	Lung Diseases Research	000	5	11/21/2023	COMPETING CONTINUATION	-$200,386
														Subtotal = $457,366

Issue Date FY: 2023 ( Subtotal = $480,199 )
2023	2023	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Lung Diseases Research	003	6	7/2/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$480,199
2023	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER, THE	11937 US HWY 271	TYLER	TX	75708	SMITH	USA	Lung Diseases Research	002	5	7/1/2023	COMPETING CONTINUATION	$0
2023	2022	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER	11937 US HIGHWAY 271	TYLER	TX	75708	SMITH	USA	Lung Diseases Research	001	5	6/27/2023	COMPETING CONTINUATION	$24,350
2023	2020	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER	11937 US HIGHWAY 271	TYLER	TX	75708	SMITH	USA	Lung Diseases Research	000	4	6/27/2023	NON-COMPETING CONTINUATION	-$24,350
														Subtotal = $480,199

Issue Date FY: 2022 ( Subtotal = $469,701 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER, THE	11937 US HWY 271	TYLER	TX	75708	SMITH	USA	Lung Diseases Research	001	5	5/15/2022	COMPETING CONTINUATION	$469,701
2022	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER, THE	11937 US HWY 271	TYLER	TX	75708	SMITH	USA	Lung Diseases Research	000	4	5/13/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $469,701

Issue Date FY: 2020 ( Subtotal = $372,859 )
2020	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER, THE	11937 US HWY 271	TYLER	TX	75708	SMITH	USA	Lung Diseases Research	000	4	8/31/2020	NON-COMPETING CONTINUATION	$372,859
														Subtotal = $372,859

Issue Date FY: 2019 ( Subtotal = $372,729 )
2019	2019	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER, THE	11937 US HWY 271	TYLER	TX	75708	SMITH	USA	Lung Diseases Research	000	3	8/12/2019	NON-COMPETING CONTINUATION	$372,729
														Subtotal = $372,729

Issue Date FY: 2018 ( Subtotal = $372,594 )
2018	2018	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER, THE	11937 US HWY 271	TYLER	TX	75708	SMITH	USA	Lung Diseases Research	000	2	9/7/2018	NON-COMPETING CONTINUATION	$372,594
														Subtotal = $372,594

Issue Date FY: 2017 ( Subtotal = $376,182 )
2017	2017	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER, THE	11937 US HWY 271	TYLER	TX	75708	SMITH	USA	Cardiovascular Diseases Research	000	1	6/2/2017	NEW	$376,182
														Subtotal = $376,182

Grand Total All Awards = $3,316,004

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Novel exosomal niches for alveolar stem cell-bassed repair of ARDS

Award Number: R01HL134828

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2017

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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