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Genomic and Functional Studies of Dysplasia-Associated Arterial Diseases

Award Number: R35HL161016
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Genomic and Functional Studies of Dysplasia-Associated Arterial Diseases - Project summary Fibromuscular dysplasia (FMD) is a non-atherosclerotic, systemic arteriopathy with excess burden on women. FMD may have varying manifestations, including hypertension, stroke and myocardial infarction, among others, depending on the arterial beds involved by arterial stenosis, aneurysm, dissection or tortuosity. Thus, the clinical diagnosis of FMD encompasses a spectrum of arterial dysplasia phenotypes, and these may be either sporadic or familial. Arterial medial fibrodysplasia underlies the pathologic arterial remodeling and susceptibility to loss of arterial integrity, and genetic susceptibility loci identified thus far implicate arterial smooth muscle and its corresponding extracellular matrix. The genetic architecture of these dysplasia- associated arterial diseases is emerging as variable, with contributions of complex genetic architecture, rare heritable variants in a subset of cases, and potential modifier genes. The proposed studies will comprehensively characterize the genetic and allelic spectrum, and test the hypothesis that the molecular and functional basis of these genetic influences, while operative in a model of locus and allelic heterogeneity, converge upon alterations of the vascular smooth muscle matricellular unit. The goal of this R35 proposal is to precisely define the genetic basis of arterial fibrodysplasia and employ relevant model systems for gene and variant mechanistic testing, resolution of genetic variants of uncertain significance, testing influences of potential modifier genes, and analysis of regulatory mechanisms, particularly those relevant to vascular sex differences. This proposal builds upon strengths in vascular disease characterization, high-throughput genetic and genomic applications, computational analysis, and molecular genetic approaches in model systems. We will conduct high throughput targeted gene sequencing to define the allelic spectrum of the involved genes in our clinical and biorepository resources, followed by hypothesis driven experiments in vascular cell and murine models for in vitro and in vivo definition of the mechanisms of the genetic findings impacting the matricellular components which are altered in arterial fibrodysplasia. The role of biologic sex and factors underlying relevant sex differences in arterial remodeling will be determined across the experiments. The outcome of this R35 and the proposed studies will be the successful integration of genomics and functional studies to provide new insights into the mechanisms of arterial dysplasia. The completion of these studies will provide critical and urgently needed biologic insights that will advance precision health objectives including disease diagnosis, prevention, and treatment, and to reduce the burden of cardiovascular morbidity and mortality.


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 = $875,727 )
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	000	5	3/9/2026	NON-COMPETING CONTINUATION	$875,727
														Subtotal = $875,727

Issue Date FY: 2025 ( Subtotal = $921,816 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	002	4	7/24/2025	NON-COMPETING CONTINUATION	$92,181
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	000	4	3/25/2025	NON-COMPETING CONTINUATION	$829,635
2025	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	001	3	6/6/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $921,816

Issue Date FY: 2024 ( Subtotal = $982,607 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	001	3	6/21/2024	NON-COMPETING CONTINUATION	$73,836
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	000	3	2/2/2024	NON-COMPETING CONTINUATION	$830,645
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	002	3	8/26/2024	SUPPLEMENT FOR EXPANSION	$78,126
														Subtotal = $982,607

Issue Date FY: 2023 ( Subtotal = $913,613 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	000	2	2/1/2023	NON-COMPETING CONTINUATION	$913,613
														Subtotal = $913,613

Issue Date FY: 2022 ( Subtotal = $921,131 )
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	000	1	1/17/2022	NEW	$921,131
														Subtotal = $921,131

Grand Total All Awards = $4,614,894

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Genomic and Functional Studies of Dysplasia-Associated Arterial Diseases

Award Number: R35HL161016

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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