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Identifying Protein-Protein Network Interactions between COPD Susceptibility Genes

Award Number: R01HL152728
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Identifying Protein-Protein Network Interactions between COPD Susceptibility Genes - PROJECT SUMMARY Genome-wide association studies (GWAS) of complex diseases like COPD have identified many genomic regions associated with disease, but the molecular mechanisms by which these genetic loci influence disease pathogenesis are largely unknown. The phenotypic effects of genetic alterations can result from disruptions of the coordinated interactions between proteins. However, the key genes within COPD GWAS loci have only been proven in a minority of those COPD GWAS regions, and network connections between the COPD GWAS gene products have rarely been identified. In this project, we will utilize COPD susceptibility genes supported by both GWAS and murine emphysema models to develop cell type-specific and disease-specific protein-protein interaction network modules related to COPD. We hypothesize that building disease network modules based on experimentally validated protein-protein interactions between COPD GWAS genes will identify novel biological connections that influence COPD-related disease processes of cell death, cellular senescence, and/or inflammation. We will perform affinity purification/mass spectrometry (AP-MS) assays of nine well-established COPD GWAS gene products. Interacting proteins that are part of network links between COPD GWAS genes based on the AP-MS assays will be further validated with co-immunoprecipitation assays. We will utilize disease network module building approaches that combine the new AP-MS experiments with existing molecular interactome data to find biological linkages between COPD GWAS gene products. We will identify cell type- specific protein-protein interaction networks by removing non-expressed genes based on RNA-Seq data in bronchial epithelial cells and alveolar macrophages, and disease-specific protein-protein interaction networks based on TOPMed RNA-Seq data from lung tissue in the Lung Tissue Research Consortium. For network paths linking COPD GWAS genes in the protein-protein interaction network, we will perturb disease network module components using CRISPR-Cas9 approaches. First, we will assess the effects of these perturbations on protein interactions of putative disease network paths. Second, we will assess the impact of these network node removal perturbations on cell-based COPD-related readouts, including cell death, cellular senescence, and inflammation. Positive phenotypic readouts in cell line experiments will be validated in primary human lung cells. This project will combine state-of-the-art computational and laboratory approaches to identify the protein-protein interaction network relationships between COPD GWAS genes within multiple lung cell types and to validate those network relationships using cell-based readouts of relevant biological processes for COPD pathogenesis.


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 = $775,224 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	4	11/28/2023	NON-COMPETING CONTINUATION	$711,942
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	001	4	6/14/2024	NON-COMPETING CONTINUATION	$63,282
														Subtotal = $775,224

Issue Date FY: 2023 ( Subtotal = $794,713 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	001	3	3/10/2023	NON-COMPETING CONTINUATION	$79,471
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	3	1/13/2023	NON-COMPETING CONTINUATION	$715,242
														Subtotal = $794,713

Issue Date FY: 2022 ( Subtotal = $794,713 )
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	2	12/23/2021	NON-COMPETING CONTINUATION	$794,713
														Subtotal = $794,713

Issue Date FY: 2021 ( Subtotal = $812,488 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	1	12/31/2020	NEW	$812,488
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	001	1	7/3/2021	NEW	$0
														Subtotal = $812,488

Grand Total All Awards = $3,177,138

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Identifying Protein-Protein Network Interactions between COPD Susceptibility Genes

Award Number: R01HL152728

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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