Fellow or Postdoc
Soheila, Ali Akbari Ghavimi, Ryan Martinez, Mariam Kerolos, Amarri Harrison, Kim de la Cruz, Marie Billaud
Marfan syndrome (MFS) is an inherited disorder that can cause thoracic aortic aneurysms. MFS is caused by genetic mutations in fibrillin-1 (FBN1) that result in the excessive activity of transforming growth factor-β (TGFβ) in vascular smooth muscle cells (vSMCs), leading to degradation of the extracellular matrix (ECM) and aortic remodeling. Therefore, regulating the release of active TGFβ in MFS can lead to novel therapeutics. TGFβ is secreted as latent complex and sequestered in ECM. Latent TGFβ is inactive and should be released via interaction with integrin αv. In this research, we explored the role of FBN1 mutation in the integrin-TGFβ interaction. Aortic specimens from MFS and healthy individuals were collected. Integrin expression and distribution were measured by RT-qPCR and immunofluorescent, respectively. Furthermore, the effect of TGFβ on integrin expression was assessed. MFS vSMCs exhibited higher expression of integrins αν, β3, β8. Integrin β8 appeared to have a prominent role in regulating latent/active TGFβ in MFS vSMCs. TGFβ stimulation decreased integrin expression, especially in MFS vSMCs. These preliminary findings suggest that upregulated integrins, particularly β8, may contribute to the increased active TGFβ observed in MFS patients. Targeting integrin ανβ8 has the potential to develop therapeutics to prevent aneurysms in MFS.
Marfan syndrome is a genetic condition that can make the main blood vessel in your body, called the aorta, weak and prone to rupture. This happens because of certain gene mutations and approximately 200,000 people in the US are affected. These mutations cause a protein called TGFβ to become too active in the cells that make up the walls of the blood vessels. This overactivity can damage the support structure of the blood vessels, leading to changes in the aorta. In our research, we are looking into ways to control the overactive TGFβ. We know that in healthy individuals, TGFβ activates after its interaction with another protein called integrins. However, our knowledge of this interaction in Marfan syndrome is limited. So, we use aortas removed from consented patients undergoing cardiac surgery and test them. Our experiments showed that these integrins are different in Marfan Syndrome compared to healthy humans. If we find a way to regulate these integrin proteins, we may develop new treatments to help prevent aortic problems in individuals with Marfan syndrome.