# Genomic and Functional Studies of Dysplasia-Associated Arterial Diseases

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $904,481

## Abstract

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.

## Key facts

- **NIH application ID:** 10773048
- **Project number:** 5R35HL161016-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** SANTHI K GANESH
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $904,481
- **Award type:** 5
- **Project period:** 2022-02-01 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10773048

## Citation

> US National Institutes of Health, RePORTER application 10773048, Genomic and Functional Studies of Dysplasia-Associated Arterial Diseases (5R35HL161016-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10773048. Licensed CC0.

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