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Multiscale Computational Models and Analysis to Understand Molecule to Organ Effects of 2'-Deoxy-ATP on Cardiovascular Function and Disease
Multiscale Computational Models and Analysis to Understand Molecule to Organ Effects of 2'-Deoxy-ATP on Cardiovascular Function and Disease
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211151512
- ISBN
- 9798384087403
- DDC
- 610
- 서명/저자
- Multiscale Computational Models and Analysis to Understand Molecule to Organ Effects of 2-Deoxy-ATP on Cardiovascular Function and Disease
- 발행사항
- [Sl] : University of California, San Diego, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 144 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-03, Section: B.
- 주기사항
- Advisor: McCulloch, Andrew D.;McCammon, James A.
- 학위논문주기
- Thesis (Ph.D.)--University of California, San Diego, 2024.
- 초록/해제
- 요약Heart failure is characterized by ventricular weakening, leading to the inability to circulate sufficient blood to the body. Despite clinical advances in recent years, heart failure remains a significant cause of morbidity and mortality within the United States and affects 6.2 million people. Clinical approaches traditionally target pathological symptoms by targeting calcium signaling and neurohormonal responses. Recently, novel therapeutics, known as myosin modulators, have shown promise by targeting the contractile machinery to regulate contractile function. To develop targeted therapeutics, detailed mechanistic models of cardiovascular function are needed which can account for deviations from normal function based on mechanisms of disease as well as therapeutics. We have developed and integrated a new framework of multiscale models that provide mechanistic insights into the mechanisms of therapeutic molecules for rescue of cardiovascular function. Specifically, we model the effects of deoxy-ATP (dATP), a known myosin activator, on motor function starting at the molecular level of function. Because dATP also has shown experimental improvements in diastolic cardiac function, we modeled and explored the molecular effects of dATP on the SERCA pump, in addition to the effects of dATP on myosin. This work highlights a new framework that captures allosteric SERCA molecular changes that influence calcium sequestration and subsequent cardiac relaxation. Molecular analysis of myosin and dATP demonstrated structural rearrangement in the region of the actin binding surface. We constructed Markov state models to quantify the nature of these changes and helps to reduce the MD simulations to more interpretable changes, which led to observed changes in the actin binding kinetics based on Brownian dynamics simulations. Allosteric changes of SERCA analyzed via generalized correlation analysis led to changes in calcium handling kinetics. The molecular effects, when propagated up in scale to tissue and organ scale, help to demonstrate improvement in cellular and ventricular function, especially in the context of heart failure. This multiscale framework highlights new methods of analysis within the context of dATP and shows promise to guide development of new highly targeted heart failure therapeutics.
- 일반주제명
- Bioengineering
- 일반주제명
- Physiology
- 일반주제명
- Biomedical engineering
- 일반주제명
- Clinical psychology
- 키워드
- Myosin
- 기타저자
- University of California, San Diego Bioengineering
- 기본자료저록
- Dissertations Abstracts International. 86-03B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520250211151512
■006m o d
■007cr#unu||||||||
■020 ▼a9798384087403
■035 ▼a(MiAaPQ)AAI31299898
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a610
■1001 ▼aHock, Marcus Terrence.
■24510▼aMultiscale Computational Models and Analysis to Understand Molecule to Organ Effects of 2'-Deoxy-ATP on Cardiovascular Function and Disease
■260 ▼a[Sl]▼bUniversity of California, San Diego▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a144 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-03, Section: B.
■500 ▼aAdvisor: McCulloch, Andrew D.;McCammon, James A.
■5021 ▼aThesis (Ph.D.)--University of California, San Diego, 2024.
■520 ▼aHeart failure is characterized by ventricular weakening, leading to the inability to circulate sufficient blood to the body. Despite clinical advances in recent years, heart failure remains a significant cause of morbidity and mortality within the United States and affects 6.2 million people. Clinical approaches traditionally target pathological symptoms by targeting calcium signaling and neurohormonal responses. Recently, novel therapeutics, known as myosin modulators, have shown promise by targeting the contractile machinery to regulate contractile function. To develop targeted therapeutics, detailed mechanistic models of cardiovascular function are needed which can account for deviations from normal function based on mechanisms of disease as well as therapeutics. We have developed and integrated a new framework of multiscale models that provide mechanistic insights into the mechanisms of therapeutic molecules for rescue of cardiovascular function. Specifically, we model the effects of deoxy-ATP (dATP), a known myosin activator, on motor function starting at the molecular level of function. Because dATP also has shown experimental improvements in diastolic cardiac function, we modeled and explored the molecular effects of dATP on the SERCA pump, in addition to the effects of dATP on myosin. This work highlights a new framework that captures allosteric SERCA molecular changes that influence calcium sequestration and subsequent cardiac relaxation. Molecular analysis of myosin and dATP demonstrated structural rearrangement in the region of the actin binding surface. We constructed Markov state models to quantify the nature of these changes and helps to reduce the MD simulations to more interpretable changes, which led to observed changes in the actin binding kinetics based on Brownian dynamics simulations. Allosteric changes of SERCA analyzed via generalized correlation analysis led to changes in calcium handling kinetics. The molecular effects, when propagated up in scale to tissue and organ scale, help to demonstrate improvement in cellular and ventricular function, especially in the context of heart failure. This multiscale framework highlights new methods of analysis within the context of dATP and shows promise to guide development of new highly targeted heart failure therapeutics.
■590 ▼aSchool code: 0033.
■650 4▼aBioengineering
■650 4▼aPhysiology
■650 4▼aBiomedical engineering
■650 4▼aClinical psychology
■653 ▼aCardiovascular mechanics
■653 ▼aMolecular dynamics
■653 ▼aMulti-scale modeling
■653 ▼aMyosin
■690 ▼a0202
■690 ▼a0541
■690 ▼a0622
■690 ▼a0719
■71020▼aUniversity of California, San Diego▼bBioengineering.
■7730 ▼tDissertations Abstracts International▼g86-03B.
■790 ▼a0033
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17161995▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
