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Defining the cellular and molecular mechanisms driving neointimal lesion growth in pulmonary hypertension

Award Number: R01HL163013
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract Pulmonary hypertension (PH) is a fatal disease of the pulmonary arteries with few supportive therapies and no cure. In PH, occlusive `neointimal lesions' grow within small pulmonary arteries and narrow vessel lumens, increasing pulmonary vascular resistance, ultimately resulting in right heart failure and death. Available PH therapies are vasodilators that do not target neointimal growth and neither prevent progression nor reverse disease. Understanding the biology of neointimal lesion growth – which cells are responsible for lesion expansion, and the pathways that control their proliferation – is key to the development of more effective therapies for pulmonary hypertension. In preliminary studies we find that proliferating neointima cells are adjacent to artery endothelial cells and have distinct gene expression that distinguishes them from cells located away from the endothelium. We hypothesize that a molecularly defined subset of neointimal cells located adjacent to the endothelium is the proliferating fraction that expands neointimal lesions, and that signals from the endothelium regulate lesion growth. Specific Aims: (1) Using proliferation tracking, genetic lineage tracing and ablation, identify and molecularly characterize the subset of neointimal cells whose proliferation is responsible for lesion growth. (2) Through bioinformatic analysis of single cell transcription in neointima and artery endothelial cells from mouse and human, identify candidate signals driving neointimal proliferation in PH and the core disease mechanisms shared between mouse and human. (3) Test the ability of a key candidate driver of neointimal proliferation for a role in lesion growth in multiple PH models. Here, by utilizing cutting edge technologies, genetics, and single cell approaches across multiple model systems, these experiments will provide a granular understanding of the cells and signals driving neointimal lesion expansion, adding substantially to the current knowledge surrounding the pathology of vascular remodeling in PH, findings we hope will ultimately lead to neointima-blocking treatment options.


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 = $651,484 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	3	1/26/2024	NON-COMPETING CONTINUATION	$598,304
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	001	3	6/21/2024	NON-COMPETING CONTINUATION	$53,180
														Subtotal = $651,484

Issue Date FY: 2023 ( Subtotal = $668,323 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	2	2/24/2023	NON-COMPETING CONTINUATION	$668,323
														Subtotal = $668,323

Issue Date FY: 2022 ( Subtotal = $668,401 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	1	3/20/2022	NEW	$668,401
														Subtotal = $668,401

Grand Total All Awards = $1,988,208

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Defining the cellular and molecular mechanisms driving neointimal lesion growth in pulmonary hypertension

Award Number: R01HL163013

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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