R35HL161016
Project Grant
Overview
Grant Description
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.
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.
Funding Goals
TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.
Grant Program (CFDA)
Awarding / Funding Agency
Place of Performance
Michigan
United States
Geographic Scope
State-Wide
Related Opportunity
Analysis Notes
Amendment Since initial award the total obligations have increased 306% from $921,131 to $3,739,167.
Regents Of The University Of Michigan was awarded
Genomic Studies of Dysplasia-Associated Arterial Diseases
Project Grant R35HL161016
worth $3,739,167
from National Heart Lung and Blood Institute in February 2022 with work to be completed primarily in Michigan United States.
The grant
has a duration of 7 years and
was awarded through assistance program 93.837 Cardiovascular Diseases Research.
The Project Grant was awarded through grant opportunity NHLBI Emerging Investigator Award (EIA) (R35 Clinical Trial Optional).
Status
(Ongoing)
Last Modified 7/25/25
Period of Performance
2/1/22
Start Date
1/31/29
End Date
Funding Split
$3.7M
Federal Obligation
$0.0
Non-Federal Obligation
$3.7M
Total Obligated
Activity Timeline
Subgrant Awards
Disclosed subgrants for R35HL161016
Transaction History
Modifications to R35HL161016
Additional Detail
Award ID FAIN
R35HL161016
SAI Number
R35HL161016-3548217243
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Public/State Controlled Institution Of Higher Education
Awarding Office
75NH00 NIH National Heart, Lung, and Blood Institute
Funding Office
75NH00 NIH National Heart, Lung, and Blood Institute
Awardee UEI
GNJ7BBP73WE9
Awardee CAGE
03399
Performance District
MI-90
Senators
Debbie Stabenow
Gary Peters
Gary Peters
Budget Funding
| Federal Account | Budget Subfunction | Object Class | Total | Percentage |
|---|---|---|---|---|
| National Heart, Lung, and Blood Institute, National Institutes of Health, Health and Human Services (075-0872) | Health research and training | Grants, subsidies, and contributions (41.0) | $1,834,744 | 100% |
Modified: 7/25/25