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A Human iPSC-based Platform to Unravel the Role of Nicotine in the Pathogenesis of Abdominal Aortic Aneurysms

Institution: Stanford University
Investigator(s): Mengcheng Shen,
Award Cycle: 2019 (Cycle 30) Grant #: T30FT0852 Award: $178,440
Subject Area: Cardiovascular and Cerebrovascular Disease
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
The aorta is the largest artery in the body, and it runs next to the spine and delivers the blood from the heart to all organs and body parts. An aortic aneurysm is a focal bulging out of the aorta due to the weakening of the aortic wall structure in that region. Aortic aneurysms can be formed at the thoracic aorta (thoracic aortic aneurysms, TAAs) or the abdominal aorta (abdominal aortic aneurysms, AAAs). Aortic aneurysms are often asymptomatic, and an acute aortic rupture or dissection occurs with >90% risk of sudden death. Due to the paucity of the understanding of the pathophysiology of aortic aneurysms, there is no approved pharmacological treatment available to prevent aneurysm formation or to stop its growth once detected. AAAs are the most common type of the disease, and are causatively affected by tobacco smoking. Smooth muscle cells (SMCs) are the predominant cell type in the aorta, and they demonstrate aortic region-dependent responses to the same pathological stimuli. However, due to the limited translational value of animal studies and the unavailability of human aortic tissues, the mechanisms by which tobacco smoking predisposes to AAAs but not to TAAs are poorly elucidated. As a surrogate disease modeling platform, human induced pluripotent stem cells (iPSCs) can be differentiated into lineage-specific SMC analogs to those in different segments of the aorta. Therefore, I will use this cell system to investigate whether region (lineage)-specific iPSC-derived SMCs will respond differently to nicotine treatment. The outcomes of this research will provide insights into the molecular mechanisms for regional propensity to the progression of AAAs in the context of tobacco smoking. Furthermore, this proposed research project will offer a proof-of-principle of using the iPSC-based platform to screen for compounds with therapeutic potentials to treatment tobacco-related cardiovascular diseases.