# Role of senescent cells in the pathogenesis of Marfan-associated cardiovascular disease

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $397,500

## Abstract

PROJECT SUMMARY
This project marks a groundbreaking first step to delineating the influence of senescent cells in the
pathogenesis of cardiovascular diseases in patients with Marfan syndrome. Affecting 1 in every 5000 live
births worldwide, with the multiple highly penetrant cardiac phenotypes (including mitral valve prolapse, aortic
valve regurgitation, and aortic aneurysms), Marfan syndrome often leads to multiple major cardiovascular
surgeries throughout a patient's life. Though it is clear that mutations in the fibrillin-1 gene and subsequent
overactivation of TGFβ signaling represent a well-defined molecular origin of Marfan syndrome, development
of therapeutic interventions that improve event-free and/or overall survival has been challenging at best.
Convention indicates that early onset of multiple cardiovascular diseases in Marfan syndrome resembles a
“progeroid-like” phenotype, and recent reports suggest that many patients develop lipodystrophy and other
phenotypes associated with chronological aging. Critically, recent studies by our research group at Mayo
(Miller/Kirkland) suggests that accumulation of senescent cells can drive progression of multiple diseases in
pre-clinical models of chronological aging and human disease. Thus, our central hypothesis—supported by
substantial preliminary data—is that accumulation of senescent cells is a major driver of increased matrix
remodeling in Marfan syndrome, and represents a novel molecular mechanism contributing to initiation and
progression of multiple pathological cardiovascular phenotypes. Thus, the aims of the current application are:
Measure and determine the effects of genetically reducing senescent cell burden on phenotypic progression
and molecular underpinnings of aortic, aortic valve, and mitral valve dysfunction in Marfanoid mice; 2)
Determine whether pharmacological clearance of senescent cells can attenuate molecular drivers and slow
phenotypic progression of aortic, aortic valve, and mitral valve dysfunction in Marfanoid mice, and 3)
Determine the distribution and burden of senescent cells in aortic, aortic valve, and mitral valve tissues from
humans with Marfan syndrome. We will use a combination of unique in vivo animal models and evaluation of
normal and Marfanoid human tissue in this application to conduct key proof-of-concept studies with genetic
clearance of senescent cells, translationally-relevant interventions in animals, and key confirmatory studies to
bridge to human disease relevance. Collectively, we aim to demonstrate that senescent cells play a significant
role in the progression of Marfan-associated cardiovascular disease, with these studies being specifically
designed to lay a foundation and justification for pursuit of early clinical trials to address this critical set of
diseases in patients with Marfan syndrome.

## Key facts

- **NIH application ID:** 9889168
- **Project number:** 5R01HL141819-03
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Jordan D Miller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $397,500
- **Award type:** 5
- **Project period:** 2018-03-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9889168

## Citation

> US National Institutes of Health, RePORTER application 9889168, Role of senescent cells in the pathogenesis of Marfan-associated cardiovascular disease (5R01HL141819-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9889168. Licensed CC0.

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