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Genetics of Cellular Sensitivity to Tobacco Compounds

Principal Investigator: Manfred Boehm

Funding Mechanism: National Institutes of Health-Intramural

ID number: 252406

Award Date: 10/1/2012

Institution: National Heart Lung and Blood Institute (NHLBI)

Tobacco compounds damage vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs), often with life-threatening consequences. Tobacco’s effects on vascular integrity vary across individuals, suggesting that genetic variations contribute to differences in patient outcomes; however, the genetic components of tobacco-induced vascular disease susceptibility are unknown. The investigators will use induced pluripotent stem cell (iPSC) technology to investigate the susceptibility of patient-specific VECs and VSMCs to tobacco compounds and determine the effects of these compounds on genetically-susceptible individuals. Study aims are: (1) to determine the impact of 20 known and suspected toxic tobacco smoke compounds on patient-specific vascular cells to define individual susceptibility; and (2) to develop iPSC lines engineered for high-throughput screening of tobacco component chemicals and chemical admixtures. The investigators will generate patient-specific iPSC lines from 20 subjects (10 long-term smokers with severe coronary artery disease and 10 long-term smokers without coronary artery disease). These 20 iPSC lines will be differentiated into VECs and VSMCs in order to survey the genetic bases of vascular susceptibility/resistance to tobacco smoke. Investigators will individually test 20 tobacco smoke components for adverse effects on the iPSC lines using an 8-dose range of each chemical and a 1-5 biomarker assay endpoint. A second verification screen will contain 10 patient-specific iPSC lines from smokers unrelated to the initial patient population. Information from this study may inform the development of new biomarkers that will distinguish the impact of different tobacco products on vascular disease.

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