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Deciphering the Molecular Mechanism of Pediatric Interstitial Lung Disease to Advance Targeted Therapies

Award Number: R01HL176680
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2025
PERIOD OF PERFORMANCE END DATE: 06/30/2030

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Deciphering the Molecular Mechanism of Pediatric Interstitial Lung Disease to Advance Targeted Therapies - ABSTRACT Pediatric interstitial lung disease (ChILD) is a rare and devastating lung disease for which there are minimal disease modifying therapies. Often presenting in the first days of life with dyspnea and hypoxia, the clinical course of ChILD is progressive respiratory failure. A key barrier to developing therapies is the lack of preclinical modeling to interrogate the pathobiology. Many ChILD patients develop this irreversible disease from harboring mutations in the alveolar epithelial type 2 (AT2) cell-restricted Surfactant Protein gene (SFTPC) that cause protein misfolding. SFTPC-ChILD provides us the opportunity to develop preclinical models of ChILD with which to decipher the molecular mechanisms of the disease and test therapeutics. We developed a robust in vivo model of SFTPC-ChILD that recapitulates key clinical and pathologic features of the human disease. We have used this model and human induced pluripotent stem cell (iPSC)-based AT2s (iAT2s) from a SFTPC- ChILD patient harboring a misfolding SFTPC mutation to study the upstream AT2 events that initiate the disease. During normal postnatal lung development, AT2s plays a critical role in the alveologenesis needed for functional gas exchange through forming an ordered alveolar epithelium and by signaling with the developing alveolar mesenchyme. The central scientific premise for this proposal is that SFTPC-ChILD AT2s lose their critical lung development functions, and that gene-based therapies will restore these functions and protect against the SFTPC-ChILD lung phenotype. Leveraging our Sftpc-ChILD mouse and iAT2s models we will reveal how aberrant AT2s lead to ChILD. We will [Specific Aim 1] interrogate the anomalous development of the epithelium in ChILD by defining the impact of Sftpc-ChILD expression on AT2 postnatal alveologenesis and [Specific Aim 2] determine how Sftpc-ChILD AT2s orchestrate interstitial remodeling pathology through signaling with the mesenchyme. We will also [Specific Aim 3] test early postnatal gene-based therapeutic strategies to resolve Sftpc-ChILD AT2 dysfunction and ChILD pathology. When completed these studies will not only heighten our understanding on ChILD pathogenesis, but also meet our goal of establishing gene editing therapeutic approaches for a disease with limited treatments and no cures.


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 = $629,498 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Lung Diseases Research	000	1	9/9/2025	NEW	$629,498
														Subtotal = $629,498

Grand Total All Awards = $629,498

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Deciphering the Molecular Mechanism of Pediatric Interstitial Lung Disease to Advance Targeted Therapies

Award Number: R01HL176680

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2025

PERIOD OF PERFORMANCE END DATE: 06/30/2030

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