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Uncovering the genetically-driven differential susceptibility to chronic obstructive pulmonary disease and pulmonary fibrosis

Award Number: R01HL162813
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Uncovering the genetically-driven differential susceptibility to chronic obstructive pulmonary disease and pulmonary fibrosis - ABSTRACT Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are two devastating chronic lung diseases associated with aging and with a common environmental risk factor, cigarette smoking, but with differing physiology and pathology, which may be due to genetics. Our group has led two large-scale COPD genome-wide association studies (GWASs), identifying five loci (near FAM13A, DSP, MAPT-KANSL1, ZKSCAN1, and STN1) where the genetic variant alleles associated with an increased COPD risk are associated with a decreased IPF risk. These opposite risk loci may reside in regulatory elements that act as “molecular switches” in disease-relevant cell types that impact gene expression to shunt biologic processes toward producing a COPD or IPF end-phenotype. However, GWASs do not directly implicate the functional consequence of genetic variants or the effector genes, cell types, or gene regulatory networks through which the genetic variants are acting. MicroRNAs, which have been implicated in the pathogenesis of both COPD and IPF, modulate gene expression levels and may impact the gene regulatory networks at the opposite risk loci. The goal of this project is to define COPD/IPF opposite risk loci and describe the functional mechanisms, effector genes, and relevant lung cell types through which these opposite risk loci are acting. We hypothesize that opposite risk genetic loci for COPD and IPF are due to shared causal variants acting as molecular switches through regulatory elements affecting gene expression in specific lung cell types. Furthermore, we hypothesize that these molecular switches are marked by discrete microRNA and RNA differences as well as divergent gene regulatory networks in COPD compared to IPF lung tissue. To address these hypotheses, we propose a series of investigations starting by refining the five known COPD/IPF opposite risk loci and identifying new opposite risk loci using expanded COPD and IPF GWASs and TOPMed WGS data. Next, we will perform joint single nucleus Assay for Transposase-Accessible Chromatin sequencing (snATAC-seq) and snRNA-seq in COPD and IPF lung tissue from the Lung Tissue Research Consortium (LTRC) to predict the disease-specific and lung cell-type- specific regulatory elements and effector genes at each of the COPD/IPF opposite risk loci. We will use CRISPR interference genome editing in implicated cell types to functionally validated predicted relationships of regulatory elements to effector genes. Next, we will generate microRNA sequencing data in IPF lung tissue from the LTRC and build disease-specific gene regulatory networks integrating genetic, microRNA, and RNA data at each opposite risk locus. We will highlight therapeutic opportunities by assessing these gene regulatory networks for drug-related pathway enrichment. We will then examine the COPD- and IPF-related cellular phenotypes that result from perturbations (CRISPR interference, CRISPR activation, and microRNA targeting) of the genes in the opposite risk loci gene regulatory networks. This study will help define the pathobiology and improve our understanding of the susceptibility for the two most deadly chronic lung diseases.


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 = $786,047 )
2026	2026	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	001	4	3/25/2026	NON-COMPETING CONTINUATION	$24,064
2026	2026	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	4	2/9/2026	NON-COMPETING CONTINUATION	$761,983
														Subtotal = $786,047

Issue Date FY: 2025 ( Subtotal = $774,616 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	3	11/29/2024	NON-COMPETING CONTINUATION	$697,156
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	001	3	8/15/2025	NON-COMPETING CONTINUATION	$77,460
														Subtotal = $774,616

Issue Date FY: 2024 ( Subtotal = $743,814 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	2	12/14/2023	NON-COMPETING CONTINUATION	$683,094
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	001	2	7/11/2024	NON-COMPETING CONTINUATION	$60,720
														Subtotal = $743,814

Issue Date FY: 2023 ( Subtotal = $781,643 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	1	12/14/2022	NEW	$781,643
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	001	1	3/31/2023	NEW	$0
														Subtotal = $781,643

Grand Total All Awards = $3,086,120

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Uncovering the genetically-driven differential susceptibility to chronic obstructive pulmonary disease and pulmonary fibrosis

Award Number: R01HL162813

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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