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Genomic and Circulating Predictors of PAH response

Award Number: R01HL142720
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Genomic and Circulating Predictors of PAH response - Pulmonary arterial hypertension (PAH) is a relentless disease characterized by vascular obliteration, right heart failure and death. Although there are ten FDA-approved therapies in three classes for PAH, none is curative and approximately 40% of patients are dead within 5 years of diagnosis. There is no established approach to identify patients who will respond to a specific therapy. The goals of this proposal are to improve outcomes in PAH using precision medicine concepts through an advanced genetics and “Omics” techniques. In unselected PAH patients, there are two subsets with striking responses to therapy. One is a small subset that has a marked reduction in PAH acutely in response to vasodilators and a dramatic long-term clinical response to calcium channel blocker (CCB) therapy. We previously published that RNA expression patterns and DNA variants in idiopathic PAH patients successfully identify patients that respond to CCB therapy. The second subset is patients that have marked improvement with parenteral prostacyclin (PP) therapy. Presently, there is little insight on how to select among the three FDA-approved PAH drug classes aside from clinical metrics of disease severity and little understanding of how PP therapy improves PAH. The first funding cycle of this grant has begun to address this unmet need by focusing on predicting responses to PP therapy. We have found two potential genetic associations with prostacyclin response, one is a polygenic risk score and the other is a variant in the complement 5 (C5) gene identified through a genome wide association study. Additionally, we prospectively enrolled 40 patients with PAH initiating PP to detect molecular predictors of prostacyclin response. In our early analysis, we have found changes in T cell phenotype in patients after PP, suggesting a more “tolerant” immune phenotype after PP. Others have published an important role for T cells in promotion of PAH, but the effect of PP therapy on T cell populations is unknown. This data was supported by a similar pattern of cytokine amelioration with PP (reduced IL-17A, IL-5). We found that IFN concentration at initiation could predict transplant-free survival, suggesting that these cytokines may be used to personalize treatment for PAH. We and others have extensively studied metabolic dysfunction in PAH, but the reasons underlying this phenomenon remain elusive. Here we found that in PAH patients requiring PP, plasma glucose directly correlated with IL-17A levels in the plasma, suggesting a potential link between metabolic disease and immune cell function in PAH. We hypothesize that immune phenotypes govern prostacyclin responses and are associated with metabolic changes in PAH. We propose the following specific aims to test this hypothesis: (1) Test the hypothesis that genomic phenotypes of prostacyclin response are common in all PAH subtypes, and are associated with poorer transplant-free survival in subjects treated with prostacyclins. (2) Test the hypothesis that inflammatory phenotype defines PAH prostacyclin response. (3) Test the hypothesis that PAH immune phenotypes are associated with metabolic dysfunction and ameliorated with prostacyclin therapy.


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: 2025 ( Subtotal = $785,069 )
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Lung Diseases Research	003	6	6/26/2025	NON-COMPETING CONTINUATION	$78,506
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Lung Diseases Research	002	6	4/17/2025	NON-COMPETING CONTINUATION	$706,563
2025	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Lung Diseases Research	001	5	3/27/2025	COMPETING CONTINUATION	$3,571
2025	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Lung Diseases Research	000	4	3/27/2025	NON-COMPETING CONTINUATION	-$3,571
														Subtotal = $785,069

Issue Date FY: 2024 ( Subtotal = $785,069 )
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Lung Diseases Research	000	5	5/24/2024	COMPETING CONTINUATION	$785,069
														Subtotal = $785,069

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Lung Diseases Research	000	4	1/4/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $622,064 )
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Lung Diseases Research	000	4	9/14/2022	NON-COMPETING CONTINUATION	$622,064
														Subtotal = $622,064

Issue Date FY: 2021 ( Subtotal = $793,312 )
2021	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Lung Diseases Research	000	3	5/6/2021	NON-COMPETING CONTINUATION	$622,064
2021	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Lung Diseases Research	001	2	8/12/2021	SUPPLEMENT FOR EXPANSION	$171,248
														Subtotal = $793,312

Issue Date FY: 2020 ( Subtotal = $622,064 )
2020	2020	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Lung Diseases Research	000	2	5/18/2020	NON-COMPETING CONTINUATION	$622,064
														Subtotal = $622,064

Issue Date FY: 2019 ( Subtotal = $622,064 )
2019	2019	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Lung Diseases Research	000	1	5/6/2019	NEW	$622,064
														Subtotal = $622,064

Grand Total All Awards = $4,229,642

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Genomic and Circulating Predictors of PAH response

Award Number: R01HL142720

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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