# Mechanobiology of aortic smooth muscle cells in human iPSC-based models of Marfan Syndrome

> **NIH NIH F31** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $43,920

## Abstract

PROJECT SUMMARY
Marfan Syndrome (MFS), one of the most common heritable connective tissue disorders, affects 1 in 5,000
individuals and has destructive manifestations in multiple organ systems; notably the cardiovascular system.
MFS is an autosomal dominant disease caused by a genetic mutation in the Fibrillin-1 gene leading to aberrant
TGFβ signaling, and frequently results in aortic aneurysm, dissection, and death. Interestingly, the associated
degeneration within the aortic vessel wall almost always occurs in the aortic root or ascending aorta and not in
the descending or abdominal aorta; while this putatively reflects regional differences in hemodynamic stress,
antihypertensive treatment alone is not effective in managing aortic aneurysm in MFS. Alternatively, it is also
the case that aortic smooth muscle cells (ASMCs), which predominate the vasoactive medial layer of the
vessel wall, have heterogeneous subtypes stemming from distinct developmental germ-layers based on their
anatomical location; Neuroectoderm (NE) origin gives rise to ascending ASMCs and Paraxial mesoderm (PM)
origin gives rise to descending ASMCs. This project will use origin-specific ASMCs differentiated from induced
pluripotent stem cells (iPSCs) from patients with MFS and healthy controls to test a novel hypothesis that
developmental origin causes location-specific abnormalities in ASMCs associated with medial degeneration in
MFS. Additionally, it will explore for biomarkers of presymptomatic congenital defects in Marfan Syndrome to
identify novel targets for prophylactic therapeutic intervention. These studies will characterize phenotypic
differences in human ASMC subtypes at the cellular and tissue level with stem-cell culturing and vascular
tissue engineering techniques. Using state-of-the-art core facilities we will also conduct transcriptomic and
proteomic analysis on these cellular and tissue models to cultivate a rich biological profile for bioinformatic
analysis. Furthermore, we will develop a bioinformatics pipeline to elucidate novel prophylactic targets
inherently responsible for ascending aortic MFS-induced medial degeneration, using our uniquely combined
phenotypic, transcriptomic, and proteomic results as input. Lastly, based on our bioinformatic outputs we will
test our intervention on our human iPSC-based in vitro models and compare to treatment with Losartan, a
commonly used anti-hypertensive drug that also exhibits unique anti-remodeling properties and has shown
promise for managing the symptoms of MFS in animals and in patients. The training plan for this fellowship will
focus on technical skills, experimental design and critical analysis, critique of published scientific data, and
presentation skills. It will be achieved by regular mentor meetings, journal clubs, conference presentations, bi-
annual committee meetings, and advanced coursework. The majority of training will occur in the Costa Lab at
the Cardiovascular Research Center at ISMMS, a highly ...

## Key facts

- **NIH application ID:** 10054654
- **Project number:** 5F31HL149271-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Robert Wiener
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $43,920
- **Award type:** 5
- **Project period:** 2019-07-24 → 2022-07-23

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10054654

## Citation

> US National Institutes of Health, RePORTER application 10054654, Mechanobiology of aortic smooth muscle cells in human iPSC-based models of Marfan Syndrome (5F31HL149271-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10054654. Licensed CC0.

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