서브메뉴
검색
상세정보
Developing a Preclinical Model of Human Sunitinib Cardiotoxicity to Assess the Role of Mechanical Loading Using Engineered Cardiac- [electronic resource]
Developing a Preclinical Model of Human Sunitinib Cardiotoxicity to Assess the Role of Mechanical Loading Using Engineered Cardiac- [electronic resource]
상세정보
- 자료유형
- 학위논문(국외)
- 자관 청구기호
- 기본표목-개인명
- 표제와 책임표시사항
- Developing a Preclinical Model of Human Sunitinib Cardiotoxicity to Assess the Role of Mechanical Loading Using Engineered Cardiac - [electronic resource] / Truitt, Rachel Elizabeth.
- 발행, 배포, 간사 사항
- 발행, 배포, 간사 사항
- 형태사항
- 1 online resource(128 p)
- 일반주기
- Source: Dissertation Abstracts International, Volume: 78-12(E), Section: B.
- 일반주기
- Adviser: Kenneth B. Margulies.
- 학위논문주기
- Thesis (Ph.D.)--University of Pennsylvania, 2017.
- 이용제한주기
- This item is not available from ProQuest Dissertations & Theses.
- 요약 등 주기
- 요약Sunitinib, a multi-targeted oral tyrosine kinase inhibitor used to treat many solid tumors, has led to important survival gains. However, this agent carries a significant risk of cardiotoxicity, with left ventricular dysfunction reported in up to 9.7% of treated individuals, and hypertension in 11--43%. There are a number of proposed mechanisms for sunitinib cardiotoxicity, however the relative contribution of each remains poorly understood. In particular, the relationship between increased left ventricular afterload toward inducing cardiac dysfunction remains unknown. Shortcomings of conventional cell culture and rodent models have hampered the identification of pivotal mechanisms of cardiotoxicity such as increased afterload. We instead chose to utilize a recently developed 3D in vitro microtissue model, where rat myocytes self-assemble to form microtissues.
- 요약 등 주기
- 요약Our model of human sunitinib cardiotoxicity recapitulated characteristics observed by other research groups, specifically, cardiomyocyte death, decreases in force generation and spontaneous beating, and demonstrated the dependence of these characteristics on sunitinib dose and treatment duration. Additionally, we observed decreases in mitochondrial membrane potential consistent with findings of mitochondrial abnormalities in patient biopsies. We demonstrated that increased in vitro afterload augments sunitinib cardiotoxicity. Finally, we created microtissues from cardiomyocytes derived from human pluripotent stem cells and found that afterload is required for sunitinib induced apoptosis at clinically relevant exposure concentrations.
- 요약 등 주기
- 요약Our finding that afterload is a key mediator suggests that anti-hypertensive therapy may be important for avoiding eventual LV dysfunction in patients treated with sunitinib.
- 주제명부출표목-일반주제명
- 주제명부출표목-일반주제명
- 부출표목-단체명
- 기본자료저록
- Dissertation Abstracts International. 78-12B(E).
- 기본자료저록
- Dissertation Abstract International
- 전자적 위치 및 접속
- 원문정보보기
- 소장사항
-
20180515 2018
MARC
008180601s2017 us esm 001c eng■001MOKWON01258921
■00520180518093808
■007cr
■020 ▼a9780355082098
■035 ▼a(MiAaPQ)AAI10270426
■035 ▼a(MiAaPQ)upenngdas:12702
■040 ▼aMiAaPQ▼cMiAaPQ
■090 ▼a전자도서(박사논문)
■1001 ▼aTruitt, Rachel Elizabeth.
■24510▼aDeveloping a Preclinical Model of Human Sunitinib Cardiotoxicity to Assess the Role of Mechanical Loading Using Engineered Cardiac▼h[electronic resource]▼cTruitt, Rachel Elizabeth.
■260 ▼a[Sl]▼bUniversity of Pennsylvania▼c2017
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2017
■300 ▼a1 online resource(128 p)
■500 ▼aSource: Dissertation Abstracts International, Volume: 78-12(E), Section: B.
■500 ▼aAdviser: Kenneth B. Margulies.
■5021 ▼aThesis (Ph.D.)--University of Pennsylvania, 2017.
■506 ▼aThis item is not available from ProQuest Dissertations & Theses.
■520 ▼aSunitinib, a multi-targeted oral tyrosine kinase inhibitor used to treat many solid tumors, has led to important survival gains. However, this agent carries a significant risk of cardiotoxicity, with left ventricular dysfunction reported in up to 9.7% of treated individuals, and hypertension in 11--43%. There are a number of proposed mechanisms for sunitinib cardiotoxicity, however the relative contribution of each remains poorly understood. In particular, the relationship between increased left ventricular afterload toward inducing cardiac dysfunction remains unknown. Shortcomings of conventional cell culture and rodent models have hampered the identification of pivotal mechanisms of cardiotoxicity such as increased afterload. We instead chose to utilize a recently developed 3D in vitro microtissue model, where rat myocytes self-assemble to form microtissues.
■520 ▼aOur model of human sunitinib cardiotoxicity recapitulated characteristics observed by other research groups, specifically, cardiomyocyte death, decreases in force generation and spontaneous beating, and demonstrated the dependence of these characteristics on sunitinib dose and treatment duration. Additionally, we observed decreases in mitochondrial membrane potential consistent with findings of mitochondrial abnormalities in patient biopsies. We demonstrated that increased in vitro afterload augments sunitinib cardiotoxicity. Finally, we created microtissues from cardiomyocytes derived from human pluripotent stem cells and found that afterload is required for sunitinib induced apoptosis at clinically relevant exposure concentrations.
■520 ▼aOur finding that afterload is a key mediator suggests that anti-hypertensive therapy may be important for avoiding eventual LV dysfunction in patients treated with sunitinib.
■590 ▼aSchool code: 0175.
■650 4▼aBiomedical engineering
■650 4▼aBioengineering
■690 ▼a0541
■690 ▼a0202
■71020▼aUniversity of Pennsylvania▼bBioengineering.
■7730 ▼tDissertation Abstracts International▼g78-12B(E).
■773 ▼tDissertation Abstract International
■790 ▼a0175
■791 ▼aPh.D.
■792 ▼a2017
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T14822873▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
■980 ▼a20180515▼f2018
