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Utilizing induced pluripotent stem cells to study the role of alveolar type 2 cell dysfunction in pulmonary fibrosis

Award Number: K08HL163494
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Utilizing induced pluripotent stem cells to study the role of alveolar type 2 cell dysfunction in pulmonary fibrosis - Project Summary This proposal details a 5-year career development training program focused on developing a patient-specific induced pluripotent stem cell (iPSC) model system to study the role of alveolar epithelial type 2 (AT2) cell dysfunction at the inception of pulmonary fibrosis (PF). A growing literature now implicates alveolar epithelial dysfunction as playing a role in the events that lead to downstream fibroblast activation culminating in relentless fibrosis in a variety of interstitial lung disease (ILD) syndromes, including adult idiopathic PF (IPF) and childhood ILD (chILD). However, without access to patient-specific human epithelial-mesenchymal model systems, there are limited options for testing hypotheses of how AT2 cell dysfunction leads to disease in humans. The outlined proposal builds on an in vitro human model system recently developed and published by the candidate to better understand the mechanisms by which AT2 cell dysfunction in the context of the most common disease- associated SFTPC variant (SFTPCI73T) leads to PF. The mechanisms identified by studying AT2 cell dysfunction using the in vitro iPSC-derived model will be further validated in vivo in SftpcI73T mutant mice. More specifically, the aims of this proposal are to: 1) study the role of AT2 cell dysfunction and the downstream consequences of epithelial dysfunction in eliciting a fibrotic cascade by utilizing a novel human patient-specific iPSC in vitro epithelial-mesenchymal recombinant model system, 2) test the hypothesis that AT2 cell-intrinsic perturbations characterized by proteostasis defects and metabolic reprograming result in impaired AT2-to-AT1 cell differentiation, inflammatory activation, and fibrogenic mesenchymal activation, and 3) identify druggable pathways for novel PF therapies by testing novel approaches to restore AT2 cell proteostasis and mitochondrial function. Both the model system to be developed and the pathogenic mechanisms to be revealed likely will be generalizable to a broad diversity of PF phenotypes, providing novel druggable targets for both familial and sporadic PF therapies. Dr. Alysandratos has 80% protected time from the Division of Pulmonary, Allergy, Sleep & Critical Care Medicine and the Boston University Department of Medicine. His mentor, Dr. Darrell Kotton at the Center for Regenerative Medicine (CReM), is an international expert in stem cell biology with a focus on applying stem cells to model and understand lung development and disease, making him ideally suited for this career development award focused on iPSC-model systems of PF. A team of extraordinary scientific advisory members, each bringing their specific expertise, has been carefully assembled to provide complementary guidance. A detailed training plan is presented that includes mentored research, didactic coursework, presentations at meetings, and a timeline for completion of the research aims, preparation of manuscripts, and future R01 application. At the completion of this proposal, the candidate will have developed the necessary expertise to successfully transition into an independent physician-scientist.


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 = $162,216 )
2026	2026	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	000	4	2/12/2026	NON-COMPETING CONTINUATION	$162,216
														Subtotal = $162,216

Issue Date FY: 2025 ( Subtotal = $162,216 )
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	000	3	12/13/2024	NON-COMPETING CONTINUATION	$162,216
														Subtotal = $162,216

Issue Date FY: 2024 ( Subtotal = $162,216 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	000	2	12/18/2023	NON-COMPETING CONTINUATION	$162,216
														Subtotal = $162,216

Issue Date FY: 2023 ( Subtotal = $162,216 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	000	1	12/27/2022	NEW	$162,216
														Subtotal = $162,216

Grand Total All Awards = $648,864

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Utilizing induced pluripotent stem cells to study the role of alveolar type 2 cell dysfunction in pulmonary fibrosis

Award Number: K08HL163494

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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