Saturday, November 23, 2024 11/23/2024

Novel mechanisms of obliterative pulmonary vascular remodeling and severe pulmonary arterial hypertension

Award Number: R01HL133951
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Pulmonary arterial hypertension (PAH) is characterized by progressive increase of pulmonary vascular resistance and obliterative vascular remodeling that causes right heart failure and premature death. Given the underlying molecular mechanisms of obliterative vascular remodeling remain enigmatic, current therapies have not targeted the fundamental disease modifying mechanisms and hence only resulted in a modest improvement in the morbidity and mortality. We have recently shown that Egln1Tie2Cre mice exhibit unprecedented spontaneous severe PAH and obliterative pulmonary vascular remodeling including neointima formation, and vascular occlusion as seen in patients with idiopathic PAH (IPAH) and PHD2 expression is diminished in ECs of occlusive pulmonary vessels of IPAH patients. This renewal proposal is based on our fundamental new observations that 1) genetic depletion of macrophages (Mφ) with the MaFIA mice inhibited obliterative vascular remodeling and attenuated PAH in Egln1Tie2Cre/MaFIA mice; 2) Single cell RNA sequencing analysis identified an emerging subpopulation of PAH-specific progenitor Mφ in Egln1Tie2Cre lungs; 3) CD206+ Mφ accumulated in the vascular lesions of Egln1Tie2Cre lungs expressed abundantly angiogenic factors inducing PASMC proliferation; 4) genetic disruption of the GPCR-dependent p110γ isoform of PI3K in Egln1Tie2Cre mice inhibited the production of these factors and obliterative vascular remodeling. Thus, we hypothesize that marked accumulation of CD206+ Mφ derived from progenitor Mφ in pulmonary vascular lesions induces obliterative pulmonary vascular remodeling and severe PAH through p110γPI3K-dependent induction of pro-PAH factors via EC-Mφ interaction. Studies in Aim 1 will determine the fundamental role of CD206+ Mφ subpopulation in promoting obliterative pulmonary vascular remodeling and severe PAH. We will employ single cell RNA sequencing, lineage tracing and genetic depletion approaches to determine the causal role of CD206+ Mφ and pMφ in mediating obliterative pulmonary vascular remodeling. In Aim 2, we will delineate the molecular basis of CD206+ Mφ in mediating obliterative pulmonary vascular remolding and explore the translational potential of targeting these molecular mechanisms for treatment of PAH. The molecular mechanisms identified in mouse models will be validated in SuHx PAH rats. The clinical relevance will also be determined with PASMCs and lung tissues of IPAH patients. We expect that the proposed studies have significant translational potential by delineating the molecular and cellular mechanisms of obliterative vascular remodeling, identifying druggable targets, and exploring novel pharmacological agents that can pharmacologically inhibit/reverse vascular remodeling for the prevention and treatment of PAH in patients.


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 = $618,533 )
2024	2024	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	000	8	5/17/2024	NON-COMPETING CONTINUATION	$618,533
														Subtotal = $618,533

Issue Date FY: 2023 ( Subtotal = $630,852 )
2023	2023	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	001	7	6/14/2023	NON-COMPETING CONTINUATION	$631,156
2023	2019	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	000	4	11/21/2022	NON-COMPETING CONTINUATION	-$304
														Subtotal = $630,852

Issue Date FY: 2022 ( Subtotal = $631,156 )
2022	2022	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	001	6	8/5/2022	NON-COMPETING CONTINUATION	$631,156
2022	2019	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	000	4	12/21/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $631,156

Issue Date FY: 2021 ( Subtotal = $631,156 )
2021	2021	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	000	5	8/17/2021	COMPETING CONTINUATION	$631,156
														Subtotal = $631,156

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	000	4	8/27/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $520,864 )
2019	2019	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	000	4	6/25/2019	NON-COMPETING CONTINUATION	$520,864
														Subtotal = $520,864

Issue Date FY: 2018 ( Subtotal = $534,114 )
2018	2018	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Cardiovascular Diseases Research	001	3	4/30/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$527,938
2018	2018	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Cardiovascular Diseases Research	002	3	5/11/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$6,176
2018	2018	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Cardiovascular Diseases Research	005	3	5/24/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$718,217
2018	2017	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	004	2	5/24/2018	NON-COMPETING CONTINUATION	-$679,575
2018	2017	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	2	4/29/2018	NON-COMPETING CONTINUATION	$0
2018	2016	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	003	1	5/24/2018	NEW	-$38,642
														Subtotal = $534,114

Issue Date FY: 2017 ( Subtotal = $679,575 )
2017	2017	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	2	6/13/2017	NON-COMPETING CONTINUATION	$679,575
														Subtotal = $679,575

Issue Date FY: 2016 ( Subtotal = $679,575 )
2016	2016	UNIVERSITY OF ILLINOIS AT CHICAGO	890 SOUTH MARSHFIELD AVENUE	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	1	5/27/2016	NEW	$679,575
														Subtotal = $679,575

Grand Total All Awards = $4,925,825

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Novel mechanisms of obliterative pulmonary vascular remodeling and severe pulmonary arterial hypertension

Award Number: R01HL133951

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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