Structural Dynamics of Cardiac Muscle Calcium ATPase Regulation
心肌钙 ATP 酶调节的结构动力学
基本信息
- 批准号:10474966
- 负责人:
- 金额:$ 77.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-01 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:ATP HydrolysisATP phosphohydrolaseAcademiaAffectAlzheimer&aposs DiseaseAmino Acid SequenceArrhythmiaBackBiochemicalBiological AssayBiologyBiophysical ProcessBiophysicsBiosensorCa(2+)-Transporting ATPaseCalciumCardiacCatalysisCellsCellular AssayCellular biologyChemicalsChimeric ProteinsClinicalCollaborationsComputer SimulationCrystallographyCysteineDataDetectionDiabetes MellitusDiseaseDwarfismEngineeringEnzymesEquilibriumFluorescenceFluorescence Resonance Energy TransferFluorescent ProbesFutureGoalsHealthHeartHeart DiseasesHeart failureHumanIndustryKineticsLabelLipidsMalignant NeoplasmsMediatingMembraneMembrane ProteinsMetabolic DiseasesMethodsModelingMolecularMolecular GeneticsMotionMotivationMuscleMuscle CellsMuscular DystrophiesMutagenesisMutationMyocardiumNerve DegenerationObesityOpen Reading FramesOpticsParkinson DiseasePeptidesPhosphorylationPhysiologicalPlayProtein IsoformsProteinsPublic HealthPumpReaderRegulationResearchResolutionRoentgen RaysRoleSERCA2aSarcoplasmic ReticulumScanningScientistSiteSkeletal MuscleSpectrum AnalysisSpin LabelsStructural ModelsStructureTechniquesTechnologyTestingTherapeuticTimeTranslatingTranslational ResearchWorkbiophysical techniquesdesigngenetic regulatory proteinhigh throughput screeninginnovationinsightnext generationnovelphospholambanprotein structurereconstitutionsarcolipinsarcopeniascreeningsmall moleculesynergismtargeted treatmenttherapeutic developmenttherapeutic targettherapeutically effectivetool
项目摘要
Project Summary/Abstract
To create a roadmap for rational therapeutic design targeting Ca dysregulation, associated with heart failure
and arrhythmia, we seek to understand the protein interactions and structural dynamics that regulate active Ca
transport in cardiac muscle. Previous work focused on two membrane proteins, the sarcoplasmic reticulum
(SR) Ca-ATPase (SERCA), in both skeletal and cardiac muscle, and its principal cardiac peptide subunit
regulator: phospholamban (PLB). The project now focuses on the heart (SERCA2a isoform) and extends to
additional peptide regulators. Our core technology is site-directed spectroscopy, in both purified proteins
and living cells. We develop and apply innovative and complementary methods in site-directed labeling,
fluorescence, EPR, and crystallography, with results integrated by computational simulations and function
in biochemical and cellular assays. Aims 1&2 identify fundamental mechanisms, while Aim 3 combines
these techniques and resultant insights to develop biophysical assays for therapeutic design. Aim 1
focuses on the functional dynamics of SERCA2a and its key structural transitions that mediate catalytic
mechanism, focusing on steps that are critical for regulation in the heart. Added emphasis is now placed on
detection of transient structural kinetics, using stopped-flow FRET methods pioneered by our lab, to directly
relate SERCA structure and function. Aim 2 investigates mechanisms by which SERCA is regulated by three
cardiac peptide subunits: PLB, sarcolipin (SLN), and DWORF. Aim 3 employs the insights of Aims 1&2 and
our breakthroughs in high-throughput fluorescence detection, to implement novel small-molecule screening
assays, with the ultimate goal of therapeutic discovery for heart disease. New compounds identified in Aim 3
feed back to provide mechanistic insight in Aims 1&2. Thus our Aims are synergistic, strengthening each
other with new insights and hypotheses, yet not interdependent, since feasibility has been established
independently for each Aim and sub-Aim. This project brings together a powerful and complementary
combination of techniques and concepts, from biophysics to chemical biology to molecular genetics to cell
biology, performed by a highly-integrated collaborative team, now adding a subcontract (Zima) to further
enhance cellular and physiological relevance. The project remains grounded in fundamental biophysical
mechanisms, and continues to exploit the recognized value of SERCA Ca pumps as therapeutic targets for
major unmet needs in public health, targeting not only the heart, but also skeletal muscle (muscular
dystrophy, sarcopenia), neurodegeneration (Alzheimer’s, Parkinson’s), and metabolic disease (diabetes,
obesity). Thus, the significance of our work extends well beyond the heart. Our biophysical approaches
will surely play a crucial role in understanding SERCA regulation, and also in controlling these functions.
Our collaborators and consultants include scientists with expertise in therapeutic development, from academia
and industry, and this project continues to stimulate separate efforts in truly translational research.
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项目总结/文摘
项目成果
期刊论文数量(0)
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RAZVAN LIVIU CORNEA其他文献
RAZVAN LIVIU CORNEA的其他文献
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{{ truncateString('RAZVAN LIVIU CORNEA', 18)}}的其他基金
Drug Discovery Pipeline Targeting Pathologically Leaky Calcium Release Channels in Age-Related Indications
针对年龄相关适应症中病理性渗漏钙释放通道的药物研发管线
- 批准号:
10157143 - 财政年份:2021
- 资助金额:
$ 77.31万 - 项目类别:
Structural Dynamics of Cardiac Muscle Calcium ATPase Regulation
心肌钙 ATP 酶调节的结构动力学
- 批准号:
10153857 - 财政年份:2020
- 资助金额:
$ 77.31万 - 项目类别:
Structural Dynamics of Cardiac Muscle Calcium ATPase Regulation
心肌钙 ATP 酶调节的结构动力学
- 批准号:
9981062 - 财政年份:2020
- 资助金额:
$ 77.31万 - 项目类别: