Human induced pluripotent stem cell-derived cardiomyocytes model cardiovascular disease and predict chemotherapeutic cardiotoxicity
Abstract/Contents
- Abstract
- Human induced pluripotent stem cells (hiPSCs) have emerged as a novel tool for drug discovery and therapy in cardiovascular medicine. These hiPSCs can be derived autologously without the ethical challenges associated with human embryonic stem cells. The use of hiPSC-derived cardiomyocytes (hiPSC-CMs) to explore cellular mechanisms of cardiovascular diseases in vitro has proven to be extremely valuable. Furthermore, patient-derived hiPSC-CMs are now providing new insights regarding drug efficacy and toxicity. In this thesis, I present novel applications of hiPSC-CMs for cardiac disease modeling in vitro and as a platform for drug validation. The first project presented in this thesis concerns viral myocarditis, a life-threatening illness that may lead to heart failure or cardiac arrhythmias. A major causative agent for viral myocarditis is the B3 strain of coxsackievirus, a positive-sense RNA enterovirus. I examined whether hiPSC-CMs could be used to model the pathogenic processes of coxsackievirus-induced viral myocarditis and to screen antiviral therapeutics for efficacy. The second project in this thesis concerns the cardiotoxicity of tyrosine kinase inhibitors (TKIs), which, despite their effectiveness as chemotherapeutic agents, are associated with cardiotoxic side-effects ranging from induced arrhythmias to heart failure. Advances in stem cell biology have enabled the development of human cardiac platforms for screening pharmacological cardiotoxicity in a high-throughput fashion in vitro. I utilized patient-specific hiPSC-CMs to screen FDA-approved TKIs in vitro for cardiotoxicities manifesting as alterations in cardiomyocyte viability, contractility, and intracellular signaling. With this data, we generated a "cardiac safety index" to assess the cardiotoxicities of existing TKIs. Therefore, hiPSC-CMs hold immense translational potential for cardiovascular disease modeling and drug screening.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2016 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Sharma, Arun |
|---|---|
| Associated with | Stanford University, Interdisciplinary Stem Cell Biology and Regenerative Medicine. |
| Primary advisor | Wu, Joseph M |
| Thesis advisor | Wu, Joseph M |
| Thesis advisor | Longaker, Michael T |
| Thesis advisor | Red-Horse, Kristy |
| Advisor | Longaker, Michael T |
| Advisor | Red-Horse, Kristy |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Arun Sharma. |
|---|---|
| Note | Submitted to the Interdisciplinary Stem Cell Biology and Regenerative Medicine. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2016. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2016 by Arun Sharma
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