자료유형  

 학위논문

Control Number  

0016931675

International Standard Book Number  

9798379711467

Dewey Decimal Classification Number  

610

Main Entry-Personal Name  

Clark, Alexander Phillip.

Publication, Distribution, etc. (Imprint  

[S.l.] : Cornell University., 2023

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2023

Physical Description  

1 online resource(228 p.)

General Note  

Source: Dissertations Abstracts International, Volume: 84-12, Section: B.

General Note  

Advisor: Christini, David;Krogh-Madsen, Trine.

Dissertation Note  

Thesis (Ph.D.)--Cornell University, 2023.

Restrictions on Access Note  

This item must not be sold to any third party vendors.

Summary, Etc.  

요약Cardiovascular disease is the leading cause of death in the United States, with over 10% of these deaths attributed to cardiac arrhythmias. We believe novel arrhythmia therapies developed over the coming decades have the potential to substantially improve patient outcomes through the use of increasingly sophisticated precision medicine tools. One such tool - induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) - provides a laboratory model for patient-specific investigations. These iPSC-CMs are currently used at academic medical centers to study arrhythmia mechanisms, and by pharmaceutical companies to study the proarrhythmic potential of drugs before clinical trials. While promising, these cells are also limited by their relatively immature electrophysiological phenotype and cell-to-cell heterogeneity. Such shortcomings have adversely affected the reproducibility, consistency, and depth of insights from studies with these cells.In this thesis, we develop a novel approach called rapid ionic current phenotyping (RICP) that can be used to investigate the sources and extent of electrophysiological heterogeneity during iPSC-CM patch-clamp experiments. We use this method to study variations in physiology and patch clamp experimental artifact conditions that lead to the heterogeneous phenotype of iPSC-CMs. Based on these findings, we propose best practice methods to mitigate sources of electrophysiological heterogeneity during experiments and address their knock-on effects during post-processing. We use the RICP method in a drug cardiotoxicity screening pipeline, showing how we can acquire surrogate markers of cardiotoxicity and identify proarrhythmia mechanisms from the same iPSC-CM. Finally, we extend the RICP approach for use in an automated patch clamp system to demonstrate its potential in a high throughput setup that is more scalable in an industry setting. Ultimately, we believe RICP, together with insights it has provided in this thesis, has the potential to affect basic science arrhythmia research, and impact the way drugs are screened.

Subject Added Entry-Topical Term  

Biomedical engineering.

Subject Added Entry-Topical Term  

Pathology.

Subject Added Entry-Topical Term  

Pharmaceutical sciences.

Index Term-Uncontrolled  

Arrhythmia

Index Term-Uncontrolled  

Cardiovascular disease

Index Term-Uncontrolled  

iPSC-CM

Index Term-Uncontrolled  

Rapid ionic current phenotyping

Index Term-Uncontrolled  

Drugs

Added Entry-Corporate Name  

Cornell University Biomedical Engineering

Host Item Entry  

Dissertations Abstracts International. 84-12B.

Host Item Entry  

Dissertation Abstract International

Electronic Location and Access  

로그인을 한후 보실 수 있는 자료입니다.

Control Number  

joongbu:642844