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Lung Allograft Stem Cell Regeneration and Immune Destruction

Award Number: K99HL155843
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Lung Allograft Stem Cell Regeneration and Immune Destruction - PROJECT SUMMARY: End-stage lung disease is the third leading cause of death worldwide. Lung transplantation is often the only option for patients with advanced lung disease, yet 50% of recipients die within five years due to the development of chronic lung allograft dysfunction (CLAD). This project seeks to examine the basis for the loss of region-specific stem cells and impaired airway regeneration, with a long-term goal of improving cell-based regenerative medicine approaches. We will make use of innovative transgenic ferret models in our well-established orthotopic lung transplantation model. We will investigate the role of glandular myoepithelial cells (MECs) in renewing submucosal gland (SMG) cells and generating abnormal surface basal stem cells (BSCs) in CLAD. We hypothesize that sustained regenerative pressures drive MECs to exit their SMG stem cell niche to reconstitute surface BSCs with abnormal lineage properties that promote an immune response. Additionally, this project will determine the regenerative function of KRT7+ glandular duct cells (DCs) during the progression of CLAD. We hypothesize that the gland duct is a maturation point for MEC stem cells to adopt a surface BSCs phenotype that is bypassed under sustained regenerative stresses in CLAD. Finally, we will determine the relationship of antigen-experienced B-cells in promoting alloimmune and autoimmune reactions against airway stem cells to drive CLAD. We hypothesize that prolonged regeneration of surface BSCs by reserve MEC stem cells leads to the retention of MEC proteins on the airway surface. This ectopic expression of self-antigens promotes an autoimmune response against the SMG stem cells niche. Currently, end-stage lung disease is a significant cause of morbidity. However, we expect that by clarifying the processes that deplete stem cells in transplanted lungs, we will improve the likelihood of developing long-term objectives of developing effective stem cell therapies to sustain lung function and resilience to prevent CLAD.


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: 2024 ( Subtotal = -$526 )
2024	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Lung Diseases Research	000	2	5/10/2024	NON-COMPETING CONTINUATION	-$526
														Subtotal = -$526

Issue Date FY: 2023 ( Subtotal = $88,975 )
2023	2023	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Lung Diseases Research	000	2	12/27/2022	NON-COMPETING CONTINUATION	$88,975
														Subtotal = $88,975

Issue Date FY: 2022 ( Subtotal = $89,947 )
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Lung Diseases Research	000	1	12/31/2021	NEW	$89,947
														Subtotal = $89,947

Grand Total All Awards = $178,396

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Lung Allograft Stem Cell Regeneration and Immune Destruction

Award Number: K99HL155843

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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