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Cellular and molecular mechanisms of alveolar repair

Award Number: R01HL167410
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Cellular and molecular mechanisms of alveolar repair - PROJECT SUMMARY Death or chronic lung dysfunction from acute respiratory distress syndrome (ARDS) is a dreaded consequence of acute injury to the alveolar gas exchange region of lung. Other than antibiotics for bacterial pneumonia and in some cases anti-inflammatory medications like corticosteroids, there are no specific therapies beyond supplementary oxygen and ventilatory support. Thus, there is an urgent need to better understand how acute alveolar injury is repaired and in cases when this is insufficient, what are the reasons for the failure to recover gas exchange function. Once the precise cellular and molecular regenerative and maladaptive alveolar responses are identified, we can move on to rationally engineer novel and specific treatments to promote repair. We have recently mapped at high resolution the alveolar regenerative response to alveolar epithelial type I (AT1) cell ablation, which revealed several unexpected mechanisms. In addition to conventional AT2 stem cell proliferation, we identified two other regenerative mechanisms. The first was immediate transdifferentiation of AT2 cells without prior proliferation, followed by mitosis of resident binucleated AT2 progenitors found in healthy lungs. We also identified pathological responses from repeated AT1 cell ablation consisting of excessive AT2 stem cell proliferation with loss of surfactant function and impaired AT1 cell differentiation. Here, we plan to flesh out the molecular and cellular regulation of these regenerative programs and to determine their physiological impact on maintaining proper gas exchange by preventing capillary leak and pulmonary edema. In summary, we will apply precise cell type ablation and injury with state-of-the-art experimental approaches to clarify at high temporal resolution the cellular and molecular basis of alveolar epithelial repair.


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 = $673,485 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	3	5/15/2025	NON-COMPETING CONTINUATION	$673,485
														Subtotal = $673,485

Issue Date FY: 2024 ( Subtotal = $672,139 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	2	5/10/2024	NON-COMPETING CONTINUATION	$672,139
														Subtotal = $672,139

Issue Date FY: 2023 ( Subtotal = $673,790 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	1	7/21/2023	NEW	$673,790
														Subtotal = $673,790

Grand Total All Awards = $2,019,414

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Cellular and molecular mechanisms of alveolar repair

Award Number: R01HL167410

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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