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Characterization of pulmonary progenitor cell dysfunction in COPA syndrome

Award Number: F31HL154777
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2023

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Characterization of pulmonary progenitor cell dysfunction in COPA syndrome - PROJECT SUMMARY – ABSTRACT Coatomer protein subunit alpha (COPA) syndrome is a rare, autosomal dominant, monogenic disorder that results in a multiorgan disease affecting the lungs and joints with incomplete penetrance. Patients present early in life with interstitial lung disease (ILD) and have elevated inflammatory markers and positive autoantibody titers. While treatments exist to control this aberrant immune phenotype, they do not address the unknown mechanism(s) of this disease. COPalpha is a ubiquitously expressed subunit of the coatomer protein complex I (COPI) which is responsible for retrograde transport of proteins from the Golgi to the ER. Alterations or disruptions in this pathway result in cellular stress. To date, most studies have examined the role of the immune system in the onset and progression of COPA syndrome without elucidating a cause for this disease. Therefore, we believe other cell types and processes are involved. Most COPA patients will at some point suffer from a spectrum of pulmonary disease such as bronchiolitis, ILD, and/or pulmonary fibrosis (PF). These diseases share certain pathogenic characteristics in response to cellular stress including, but not limited to, ER stress and unfolded protein response (UPR) activation, activated fibroblasts, inflammation, and aberrant autophagy. Progenitor cells of the proximal and distal lung, basal and alveolar type II cells (ATII), respectively, are disproportionally affected causing aberrant maintenance of the epithelium throughout the airway. We believe similar mechanisms of progenitor cell dysfunction are occurring in COPA syndrome patients. We therefore hypothesize that COPA syndrome is driven by an intrinsic progenitor cell defect that compromises epithelial maintenance resulting in ILD and lung fibrosis. In Aim 1, we will determine the epithelial cell- intrinsic defects resulting from the expression of COPAMT. This will be achieved by characterizing the COPalpha interactome to elucidate anomalous protein interactions leading to cellular stress. We will then characterize the transcriptome of COPAMT using single cell RNA sequencing to highlight differential gene expression patters associated with disease. Furthermore, we will utilize in vivo mouse models to accurately describe the link between pulmonary progenitor cell dysfunction and activation of the immune responses associated with COPA syndrome. In Aim 2, we will validate strategies to rescue the epithelial cell defect of COPA syndrome using lentiviral vector delivery systems and gene editing tools with the intention of rescuing the diseased phenotype.


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 = -$83,266 )
2024	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Lung Diseases Research	002	3	7/24/2024	NON-COMPETING CONTINUATION	-$38,948
2024	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Lung Diseases Research	001	2	7/24/2024	NON-COMPETING CONTINUATION	-$38,232
2024	2020	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Lung Diseases Research	000	1	7/24/2024	NEW	-$6,086
														Subtotal = -$83,266

Issue Date FY: 2022 ( Subtotal = $38,948 )
2022	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Lung Diseases Research	000	3	8/15/2022	NON-COMPETING CONTINUATION	$38,948
														Subtotal = $38,948

Issue Date FY: 2021 ( Subtotal = $38,232 )
2021	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Lung Diseases Research	000	2	8/23/2021	NON-COMPETING CONTINUATION	$38,232
														Subtotal = $38,232

Issue Date FY: 2020 ( Subtotal = $37,716 )
2020	2020	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Lung Diseases Research	000	1	8/14/2020	NEW	$37,716
														Subtotal = $37,716

Grand Total All Awards = $31,630

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Characterization of pulmonary progenitor cell dysfunction in COPA syndrome

Award Number: F31HL154777

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2023

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