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Novel roles of RNA modifications in the pathogenesis of pulmonary vascular remodeling and PAH

Award Number: R01HL162299
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Novel roles of RNA modifications in the pathogenesis of pulmonary vascular remodeling and PAH - 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. While several transcription factors and transcriptional co- activators have been studied in the context of PAH, post-transcriptional regulations of mRNAs that can affect expression of key proteins remain largely unexplored. RNA modifications including N6-methyladenosine (m6A) have recently been discovered as essential regulators of gene expression. The m6A modification controls RNA stability, transport, and translation and has been linked to human diseases such as obesity and cancers. Despite its functional importance in various fundamental bioprocesses, studies of m6A modification of mRNAs in PAH are lacking. Our Supporting Data show that expression of fat mass and obesity-associated protein (FTO), a well-characterized RNA demethylase, is markedly elevated in pulmonary vascular endothelial cells (ECs) of idiopathic PAH patients. Tie2Cre-mediated deletion of Fto in ECs (FtoTie2Cre) inhibited PH induced by chronic hypoxia. Our mechanistic studies provide evidence that several PAH-causing genes are potential FTO targets in human lung ECs. Furthermore, pharmacological inhibition of FTO in monocrotaline- challenged rats inhibited pulmonary vascular remodeling and PH. Thus, we hypothesize that endothelial FTO, as a major m6A eraser, acts as a key regulator of mRNA stability and accumulation of key PAH-causing genes in ECs to regulate pulmonary vasoconstriction and vascular remodeling and thus is a novel therapeutic target for PAH. We propose the following 3 Specific Aims. In Aim 1, we will define the fundamental role of endothelial FTO in the pathogenesis of PAH. In Aim 2, we will delineate the molecular mechanisms underlying FTO regulation of endothelial dysfunction leading to pulmonary vasoconstriction and vascular remodeling. We will identify the key FTO targets in ECs and address the possibility of rescuing the phenotype of FtoTieCre by novel nanoparticle-mediated in vivo EC-specific gene transfer. In Aim 3, we will explore the therapeutic potential of FTO inhibitors including a repurposed FDA-approved drug in the treatment of PAH employing 3 complimentary animal models of PAH. Based on the clear clinical relevance of our novel findings, we expect that the proposed studies have significant translational potential by delineating the molecular and cellular mechanisms of endothelial dysfunction leading to pulmonary vasoconstriction and vascular remodeling, identifying druggable targets, and exploring pharmacological agents that can pharmacologically inhibit/reverse vascular remodeling and also inhibit vasoconstriction for the prevention and treatment of PAH in patients. Thus, we believe the proposed studies have great translational potential.


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 = $0 )
2026	2025	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	000	4	4/27/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $660,077 )
2025	2025	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	000	4	7/10/2025	NON-COMPETING CONTINUATION	$660,077
														Subtotal = $660,077

Issue Date FY: 2024 ( Subtotal = $646,874 )
2024	2024	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	000	3	8/1/2024	NON-COMPETING CONTINUATION	$646,874
														Subtotal = $646,874

Issue Date FY: 2023 ( Subtotal = $660,077 )
2023	2023	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	000	2	8/2/2023	NON-COMPETING CONTINUATION	$660,077
														Subtotal = $660,077

Issue Date FY: 2022 ( Subtotal = $679,977 )
2022	2022	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	000	1	8/24/2022	NEW	$679,977
														Subtotal = $679,977

Grand Total All Awards = $2,647,005

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Novel roles of RNA modifications in the pathogenesis of pulmonary vascular remodeling and PAH

Award Number: R01HL162299

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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