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Gain-of-function toxicity in alpha-1 antitrypsin deficient type 2 alveolar epithelial cells

Award Number: F30HL170745
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Gain-of-function toxicity in alpha-1 antitrypsin deficient type 2 alveolar epithelial cells - Alpha-1 antitrypsin deficiency (AATD) is the sole monogenic cause of emphysema. AATD is caused by a mutation in the SERPINA1 gene, which encodes for alpha-1 antitrypsin (AAT). AAT is produced mainly in hepatocytes, from which it is secreted into the bloodstream to exert its primary function of inhibiting neutrophil elastase in the lungs. The most common disease-causing mutation results in polymerogenic AAT, known as “Z AAT”. Z AAT is trapped in the endoplasmic reticulum of hepatocytes, leading to proteotoxic liver disease and reduced circulating AAT. AATD emphysema has classically been attributed to the protease-antiprotease imbalance resulting from reduced circulating AAT. This hypothesis is complicated by two findings – 1) the supplementation of functional AAT is less effective than expected if emphysema were solely caused by loss of AAT and 2) there is evidence for Z AAT-induced proteotoxicity in extrahepatic cells. Type 2 alveolar epithelial cells (AT2s) are the progenitor cells of the distal lung, renewing both themselves and type 1 alveolar epithelial cells in response to injury. While Z AAT expression has been shown in multiple extrahepatic cell types, and recently published single cell RNA sequencing data have shown high expression of SERPINA1 in AT2s, AAT expression in AT2s remains unexplored. Our preliminary data identifies transcriptional evidence of an unfolded protein response in AT2s from explanted human PiZZ lungs. The goal of this proposal is to elucidate the functional and transcriptional impacts of Z AAT expression in AT2s, both at baseline and in the context of cigarette smoke injury, and to determine whether Z AAT expression in AT2s contributes to the pathogenesis of emphysema. Primary human AT2s are difficult to access pre-mortem. It is likewise challenging to maintain primary human AT2s in vitro, limiting studies of their biology. To solve these challenges, we will utilize the combination of a novel mouse model in Aim 1 and AATD patient-derived induced pluripotent stem cells (iPSCs) in Aim 2. In Aim 1, we will chronically expose mice expressing human Z or “normal” SERPINA1 cDNA in AT2s to cigarette smoke to investigate the accumulation of AAT and activation of the unfolded protein response in AT2s, as well as histologically examine emphysema severity and immune cell infiltration. In Aim 2, we will to generate AT2-like cells (iAT2s) from AATD patient-derived and CRISPR-corrected isogenic control iPSCs and expose them to cigarette smoke. We will determine iAT2 dysfunction and genetic disease signature by measuring AAT protein accumulation and secretion, activation of the unfolded protein response, functional capacity, and global transcriptomic response to injury. Together these Aims will produce significant advances in our understanding of AATD, and suggest the need for novel treatment strategies.


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 = $54,538 )
2026	2026	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	000	3	3/20/2026	NON-COMPETING CONTINUATION	$54,538
														Subtotal = $54,538

Issue Date FY: 2025 ( Subtotal = $54,538 )
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	000	2	11/22/2024	NON-COMPETING CONTINUATION	$53,974
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	001	2	8/7/2025	NON-COMPETING CONTINUATION	$564
														Subtotal = $54,538

Issue Date FY: 2023 ( Subtotal = $52,694 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	000	1	7/20/2023	NEW	$52,694
														Subtotal = $52,694

Grand Total All Awards = $161,770

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Gain-of-function toxicity in alpha-1 antitrypsin deficient type 2 alveolar epithelial cells

Award Number: F30HL170745

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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