# Effect of mutations in the TGF-beta pathway genes on smooth muscle cell differentiation using patient derived iPSCs.

> **NIH NIH K08** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $169,560

## Abstract

PROJECT SUMMARY/ABSTRACT
Thoracic aortic aneurysm and dissection (TAAD) is a lethal disease and there is no medical treatment to
prevent or reverse TAAD. Transforming growth factor (TGF-β) plays a critical role in syndromic and non-
syndromic TAAD. The detailed mechanism is unknown. The mutations of genes coding TGF-β receptor I and II
(TGFBR1 and TGFBR2), and SMAD3 causing TAAD are known or predicted to be Loss-of-function mutations
resulting in decrease of TGF-β signaling. However, a paradoxical elevation of TGF-β signaling was found in
the end-stage aneurysmal tissue from the patients with those mutations and Marfan Syndrome (MFS). The
increasing of TGF-β signaling in the end aneurysmal tissue was found to be independent of TGF-  or genetic
background, but due to epigenetic control. Losartan, which blocks the elevation of TGF-β signaling and
prevents TAAD in mouse models of MFS and Tgfbr1/2 mutations, does not show any more efficacy of reducing
aneurysm in MFS patients than β-blockade in a multicenter clinical trial. On the other hand, conditional
interruption of TGF-β signaling in the early life of mice results in decreased TGF-β signaling and severe TAAD.
It is unknown how the TGF-β signaling changes in smooth muscle cells (SMCs) in the early life of human with
gene mutation of TGFBR1/2 and SMAD3. It is also unknown how those mutations alter human SMC
phenotype which directly contribute to the integrity of the aorta and related to TAAD. The only model to answer
those questions is to use human induce pleuripotent stem (iPS) cells harboring those mutations to model the
TAAD of different part of aorta by differentiating iPS cells into different lineage in vivo and in vitro. The long
term goals of this project are to: 1) use a human cellular model harboring mutations of TGF-β pathway and
animal model harboring tissue engineered mutant vessel made of patients SMCs to dissect cellular and
molecular mechanisms of TAAD and 2) develop therapeutic strategies to prevent or reverse the progression of
thoracic aortic aneurysms. The objective of this proposal is to determine the effect of mutations of TGFBR1/2
and SMAD3 on the differentiation, contractility and secretory function of vascular SMCs and the underlying
mechanisms in vivo and in vitro. The central hypothesis is that the mutations of TGFBR1/2 and SMAD3 cause
defective differentiation of SMCs, resulting in an impaired contractile apparatus and secretion of extracellular
matrix (ECM) in SMCs, and aneurysm of the mutant vessels. We predict these effects will be reversed by
driving differentiation of the SMCs through pathways distinct from TGF-β, such as rapamycin.

## Key facts

- **NIH application ID:** 9940867
- **Project number:** 5K08HL130614-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Bo Yang
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $169,560
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9940867

## Citation

> US National Institutes of Health, RePORTER application 9940867, Effect of mutations in the TGF-beta pathway genes on smooth muscle cell differentiation using patient derived iPSCs. (5K08HL130614-05). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9940867. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*