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Multiscale Computational Modeling of Novel Treatments for Heart Failure With Reduced Ejection Fraction
Multiscale Computational Modeling of Novel Treatments for Heart Failure With Reduced Ejection Fraction
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211151105
- ISBN
- 9798383189955
- DDC
- 610
- 서명/저자
- Multiscale Computational Modeling of Novel Treatments for Heart Failure With Reduced Ejection Fraction
- 발행사항
- [Sl] : University of California, San Diego, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 140 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-01, Section: B.
- 주기사항
- Advisor: McCulloch, Andrew D.
- 학위논문주기
- Thesis (Ph.D.)--University of California, San Diego, 2024.
- 초록/해제
- 요약Heart failure is a major healthcare challenge, and most existing treatments mitigate its symptoms without addressing underlying mechanical dysfunction. Therefore, recent advancements aim to directly target the contractile machinery of the heart. In this work, we utilized a combination of multiscale modeling approaches spanning from the atom to whole heart to investigate the therapeutic potential of targeting proteins within the sarcomere to improve cardiac contractile function in heart failure with reduced ejection fraction. We specifically investigated 2-deoxy-ATP (dATP), a potential myosin-activating therapeutic. dATP improves cardiac function by increasing the rate of crossbridge cycling and Ca2+ transient decay. However, the molecular mechanisms of these effects and how therapeutic responses to dATP are achieved, especially for small fractions of dATP, remain poorly understood. This is especially true in heart failure, where energy metabolism is impaired. We utilized a combination of molecular dynamics (MD), Brownian dynamics (BD), and Markov state modeling, to show that dATP increases the actomyosin association rate via stabilization of pre-powerstroke myosin. We also showed using MD and BD that dATP acts on the sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) pump to accelerate Ca2+ re-uptake into the sarcoplasmic reticulum during cardiac relaxation by increasing the rate of Ca2+ association to SERCA. We then employed a spatially explicit model of the sarcomere to show that dATP increases the pool of myosin heads available for crossbridge cycling, increasing steady state force development at low dATP fractions due to mechanosensing and nearest-neighbor cooperativity. We extended our analysis to assess cardiomyocyte mechanics and excitation-contraction coupling, and found that the effects of dATP on SERCA, along with increased myosin recruitment, contributed to improved cell contraction and relaxation. These mechanisms extended to the ventricular level to improve contractility and metabolism, especially in heart failure, where our model of ventricular mechanics and circulation predicted that dATP increased ejection fraction and the energy efficiency of cardiac contraction. We finally extended our approach to demonstrate how our multiscale computational modeling approach can be utilized to provide insight into the link between genotype and phenotype in heart failure and to develop novel therapeutics.
- 일반주제명
- Bioengineering
- 일반주제명
- Biomedical engineering
- 일반주제명
- Biomechanics
- 기타저자
- University of California, San Diego Bioengineering
- 기본자료저록
- Dissertations Abstracts International. 86-01B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■020 ▼a9798383189955
■035 ▼a(MiAaPQ)AAI31143471
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a610
■1001 ▼aTeitgen, Abigail Elizabeth.
■24510▼aMultiscale Computational Modeling of Novel Treatments for Heart Failure With Reduced Ejection Fraction
■260 ▼a[Sl]▼bUniversity of California, San Diego▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a140 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-01, Section: B.
■500 ▼aAdvisor: McCulloch, Andrew D.
■5021 ▼aThesis (Ph.D.)--University of California, San Diego, 2024.
■520 ▼aHeart failure is a major healthcare challenge, and most existing treatments mitigate its symptoms without addressing underlying mechanical dysfunction. Therefore, recent advancements aim to directly target the contractile machinery of the heart. In this work, we utilized a combination of multiscale modeling approaches spanning from the atom to whole heart to investigate the therapeutic potential of targeting proteins within the sarcomere to improve cardiac contractile function in heart failure with reduced ejection fraction. We specifically investigated 2-deoxy-ATP (dATP), a potential myosin-activating therapeutic. dATP improves cardiac function by increasing the rate of crossbridge cycling and Ca2+ transient decay. However, the molecular mechanisms of these effects and how therapeutic responses to dATP are achieved, especially for small fractions of dATP, remain poorly understood. This is especially true in heart failure, where energy metabolism is impaired. We utilized a combination of molecular dynamics (MD), Brownian dynamics (BD), and Markov state modeling, to show that dATP increases the actomyosin association rate via stabilization of pre-powerstroke myosin. We also showed using MD and BD that dATP acts on the sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) pump to accelerate Ca2+ re-uptake into the sarcoplasmic reticulum during cardiac relaxation by increasing the rate of Ca2+ association to SERCA. We then employed a spatially explicit model of the sarcomere to show that dATP increases the pool of myosin heads available for crossbridge cycling, increasing steady state force development at low dATP fractions due to mechanosensing and nearest-neighbor cooperativity. We extended our analysis to assess cardiomyocyte mechanics and excitation-contraction coupling, and found that the effects of dATP on SERCA, along with increased myosin recruitment, contributed to improved cell contraction and relaxation. These mechanisms extended to the ventricular level to improve contractility and metabolism, especially in heart failure, where our model of ventricular mechanics and circulation predicted that dATP increased ejection fraction and the energy efficiency of cardiac contraction. We finally extended our approach to demonstrate how our multiscale computational modeling approach can be utilized to provide insight into the link between genotype and phenotype in heart failure and to develop novel therapeutics.
■590 ▼aSchool code: 0033.
■650 4▼aBioengineering
■650 4▼aBiomedical engineering
■650 4▼aBiomechanics
■653 ▼aCardiac biomechanics
■653 ▼aComputational modeling approach
■653 ▼aMultiscale modeling
■653 ▼aMolecular dynamics
■690 ▼a0202
■690 ▼a0541
■690 ▼a0648
■71020▼aUniversity of California, San Diego▼bBioengineering.
■7730 ▼tDissertations Abstracts International▼g86-01B.
■790 ▼a0033
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17160718▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
