The Stanford Thoracic Aortic Research Laboratory focuses on molecular mechanisms contributing to thoracic aortic aneurysm development, particularly focusing on Marfan syndrome, as well as other genetic connective tissue disorders, including Loeys-Dietz, Smad3 deficiency, ACTA2 and Bicuspid Aortic Valve. Our laboratory utilizes multiple model systems, including in vivo mouse models, in vitro cell culture, including induced-pluripotent stem (iPS) cells from human Marfan syndrome patients, and an extensive tissue bank of human aneurysm tissue to evaluate cell signaling pathways and downstream protein and gene expression analyses to uncover the mechanistic contributors to aneurysm development.
Using Stem Cells to Understand Aortic Root Aneurysms
While it has long been recognized that aortic aneurysm development in Marfan syndrome classically affects the aortic root with minimal dilatation of the ascending aorta, it remains unclear what mechanisms dictate this predilection. Some investigators have proposed that the varying embryonic origins of different aortic segments may explain this phenomenon. We have developed induced pluripotent stem cells (iPSCs) from patients with Marfan syndrome and generated aortic smooth muscle cells differentiated through multiple developmental pathways. We are currently using these cell lines to study aortic smooth muscle characteristics and responses to stimuli in embryonic origin-specific contexts to identify targets for future therapies.
Transforming Growth Factor-Beta and Hereditary Aortopathy
Enhanced transforming growth factor-beta (TGF-β) signaling is known to drive aortic aneurysm development in mouse models of Marfan syndrome, but the details of downstream mediators of this process remain unknown. We are utilizing an important mouse model of Marfan syndrome as well as our tissue bank of surgical samples and cell culture lines derived from these samples to translate animal model findings to human tissue and further delineate the effects of TGF-β on aneurysm development in Marfan syndrome and other TGF-β-related aortopathies.
Apoptosis in Aneurysm Development
We recently reported on the importance of apoptosis as an early driver of aneurysm development in Marfan syndrome (Emrich et al. ATVB 2015). Importantly, apoptosis was found to contribute to extracellular matrix remodeling and elastin degradation, which were prevented with treatment of a pan-caspase inhibitor. Furthermore, we demonstrated that TGF-β increases smooth muscle cell apoptosis in the aortic wall, thus providing a mechanism for the deleterious effects of enhanced TGF-β in Marfan syndrome.
(click thumbnails for larger images)
Aneurysm detection using Elastin-specific MRI contrast agent
Aortic aneurysms in the Marfan model are associated with degradation of elastin in the aortic wall. We discovered that there exists an elastin-specific magnetic resonance contrast agent which accurately measures elastin bound gadolinium within the aortic wall, thus able to detect a decrease in the amount of elastin, and creating a non-invasive method of assessing the severity of an aneurysm.
The Role of Reactive Oxygen Species in Aneurysm Formation in Marfan syndrome
This project utilizes the Fbn1C1039G/+ Marfan mouse model to study the role of reactive oxygen species (ROS) in the development of aortic root aneurysms. The redox state is regulated through the expression of oxidant and antioxidant enzymes, thus controlling the production of ROS as well as their scavengers. The mechanism(s) of ROS production in vascular smooth muscle cells (SMC), the main population in the aortic media wall is still not fully understood.
Histology, biochemical, protein and gene expression techniques are used to study the baseline characteristics of the aneurysmal aorta, as well as the therapeutic response to novel antioxidant drugs. We hope to further understand the role of ROS in smooth muscle cell pathology in order to further elucidate the mechanisms of aortic aneurysm development in MFS.