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-?) plays a critical role in syndromic and non- syndromic TAAD. The detailed mechanism is unknown. The mutations of genes coding TGF-? 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-? signaling. However, a paradoxical elevation of TGF-? signaling was found in the end-stage aneurysmal tissue from the patients with those mutations and Marfan Syndrome (MFS). The increasing of TGF-? 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-? 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 ?-blockade in a multicenter clinical trial. On the other hand, conditional interruption of TGF-? signaling in the early life of mice results in decreased TGF-? signaling and severe TAAD. It is unknown how the TGF-? 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-? 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-?, such as rapamycin.

Public Health Relevance

Thoracic aortic aneurysms and dissections (TAAD) is a lethal disease and there are currently no medical treatments to completely prevent or reverse this disease due to unknown mechanisms of disease development. We will use patient's own induced pluripotent stem cells to study the effect of gene mutations in TGF-??pathway genes on the smooth muscle differentiation and survival in vivo and in vitro. The study will improve our understanding of the mechanism of TAAD and help us develop novel therapies to prevent this disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
Project #
Application #
Study Section
NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
Program Officer
Carlson, Drew E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
Zip Code