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Elucidating the mechanical regulation of the lung gas exchange interface

Award Number: K99HL185935
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 06/15/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Elucidating the mechanical regulation of the lung gas exchange interface - PROJECT SUMMARY During breathing, the lung undergoes a constant, cyclical biophysical strain. This mechanical homeostasis is disrupted during numerous lung diseases including acute lung injury, contributing to lung dysfunction. Despite the importance of lung mechanics, how cells within the lung respond to mechanical cues to control tissue structure and function remains poorly understood. This proposal focuses on defining the mechanical force-driven mechanisms that regulate cells within the alveoli, the elastic gas-exchanging sacs in the distal lung. Using a novel reversible bronchial ligation model that precisely controls unilateral lung motion in mice, I have identified a transcriptionally distinct capillary endothelial cell (CAP) state in response to restrained respiratory motion. We call these cells mechanically induced CAPs or miCAPs. These miCAPs persist after the mouse lung motion is restored and require inhibited mechanosignaling within the adjacent alveolar type I (AT1) epithelial cells to arise. Importantly, miCAPs proliferate in response to elevated mechanical forces. These results support a unique fate and mechanoresponsive behavior of miCAPs. In the K99 training phase, I will use the reversible bronchial ligation model to define the molecular mechanisms that drive the specification and maintenance of miCAP fate. This work will be conducted at the University of Pennsylvania, where I will benefit from a rich intellectual environment, extensive institutional resources, and a highly collaborative scientific community, along with the full support of the institution. In the R00 phase, I will leverage two newly developed mouse lines that enable lineage tracing of mechanically sensitive cells to determine how these cells respond to pathological mechanical cues during acute lung injury. Completion of these aims will provide important insights into how mechanical forces impact lung structure and function under both homeostatic and disease conditions. In addition to the proposed scientific objectives, I have designed a structured training plan with my primary mentor, Dr. Edward Morrisey, who is a world-renowned expert in pulmonary cell biology, and assembled an advisory committee of accomplished scientists to support my transition to independence. Together, my proposed research and career development plans will advance our understanding of how mechanical forces shape lung structure and function and support my career goal of becoming an independent investigator in pulmonary cell biology and mechanobiology.


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 = $157,658 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Lung Diseases Research	000	1	6/18/2026	NEW	$157,658
														Subtotal = $157,658

Grand Total All Awards = $157,658

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Elucidating the mechanical regulation of the lung gas exchange interface

Award Number: K99HL185935

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 06/15/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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