# Marfan Aortic Embryologic Origin Influences Aneurysm Formation

> **NIH NIH R01** · STANFORD UNIVERSITY · 2022 · $654,599

## Abstract

PROJECT SUMMARY
Marfan syndrome (MFS), caused by mutations in the fibrillin-1 gene, is the most common inherited connective
tissue disorder. Patients typically develop aortic root aneurysms with ensuing aortic dissection and rupture
remaining the leading cause of death. Without prophylactic surgery, life-expectancy is reduced to age 40 years.
Novel targeted drug therapies have been absent, likely due to limitations in mechanistic understanding. Thus,
there is an urgent need to dissect the pathway(s) involved in MFS aortic wall extracellular matrix (ECM)
breakdown resulting in aneurysm formation. We hypothesize that distinct embryonic origins of SMCs populating
the aortic root contribute to aortic root-specific aneurysm pathophysiology. In the recent funding period, we
created and characterized induced-pluripotent stem cells (iPSCs) from MFS patients and differentiated them into
SMCs from each embryologic origin. We learned that the microRNA, miR-29b and related downstream genes
were dependent on SMC embryologic origin. After applying high-throughput proteomics, we also discovered that
iPSC-derived SMCs from MFS patients express distinct, lineage-specific proteomic profiles affecting critical
biologic processes including ECM synthesis/degeneration and SMC contraction/motility. Utilizing single-cell RNA
sequencing, we identified a distinct, disease-specific SMC cluster that develops transcriptomic alterations
regionally in both murine models and human aortic root aneurysms. In complimentary MFS Fbn1C1041G/+ mouse
in vivo studies, we discovered several regional upstream TGF-β-dependent triggers that ultimately increase
matrix metalloproteinase-mediated ECM remodeling, including: (a) Ras (GTPase) signaling; (b) NADPH
activation leading to reactive oxygen species production; and (c) androgen potentiation of TGF-β signaling in
male mice. Drug blockade of each discovered pathway reduced aneurysm formation.
In this renewal application, we rigorously expand our research progress by proposing several innovative
experiments to study the relative contributions of SMC lineages to regional ECM remodeling, investigate the
upstream triggers and pathologic role of modulated SMCs during aneurysm formation, and advance the
translation of disease-specific iPSC modeling for novel pathway discovery. Specific Aim 1 seeks whether
interactions between MFS SHF- and neural crest-SMCs induce synthetic SMC phenotype and ECM remodeling.
We investigate the novel role of reduced SHF-SMC mannose receptor 2 (MRC2) on ECM composition,
proteolysis and SMC contractile function. We will also elucidate the effect of ECM biomechanical properties on
lineage-specific SMC responses, including SMC transcriptomic modulation and single cell mechanical
properties. Specific Aim 2 strives to determine the effects of modulated SMC populations on ECM remodeling in
vitro using our innovative MFS decellularized matrix scaffolds. Novel lineage-tracing transgenic mouse models
will be utilized to iden...

## Key facts

- **NIH application ID:** 10366102
- **Project number:** 9R01HL157949-06A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Michael Peter Fischbein
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $654,599
- **Award type:** 9
- **Project period:** 2016-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366102

## Citation

> US National Institutes of Health, RePORTER application 10366102, Marfan Aortic Embryologic Origin Influences Aneurysm Formation (9R01HL157949-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10366102. Licensed CC0.

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