Structural analysis of oxidation effects on the hemostatic process
氧化对止血过程影响的结构分析
基本信息
- 批准号:8712549
- 负责人:
- 金额:$ 14.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-08-02 至 2018-06-30
- 项目状态:已结题
- 来源:
- 关键词:AdhesionsAdhesivenessAffectAreaAwardBindingBiological AssayBlood PlateletsClinical PathologyCoagulation ProcessComplementCytolysisDataDiseaseDrug DesignEnvironmentEnzymesEquilibriumEquipmentFacultyFiberFibrinFibrinogenGoalsHemorrhageHemostatic AgentsHemostatic functionInflammationKnowledgeLaboratoriesLateralLeadLearningLifeLightLinkLiteratureLocationManuscriptsMass Spectrum AnalysisMechanicsMentorsMentorshipMethionineMethodsMicroscopyModificationMolecularMolecular StructureMutagenesisMutationOxidantsPathologicPathologyPathway interactionsPatientsPlasmaPlatelet aggregationPositioning AttributeProcessProductionPropertyProteinsReportingResearchResourcesRiskRunningSiteStructureSupercomputingTestingTherapeuticThrombinThrombosisThrombotic Thrombocytopenic PurpuraThrombusUniversitiesWashingtonbasecareerdesigndrug discoveryinsightmethionine sulfoxidemolecular dynamicsoxidationpolymerizationpreventprotein structurepublic health relevanceresearch studysimulationskillsstructural biologyvon Willebrand Factor
项目摘要
DESCRIPTION (provided by applicant): The long-term career goal of the candidate is to investigate the structural basis of hemostasis and how external factors alter it. During the K25 award he will analyze how oxidation effects alter the structure and function of two key proteins in the hemostatic process, von Willebrand Factor and fibrin. The candidate will use molecular dynamics simulations, his main expertise, to investigate how oxidation alters the structural stability of proteins. Dr. Jim Pfaendtner, an expert in accelerated molecular dynamics methods, will serve as a co-mentor. The simulations will be complemented through microscopy experiments which the candidate will learn how to perform himself under the mentorship of Dr. Wendy Thomas. Thanks to Dr. Jose Lopez as co-mentor, the candidate will gain deep knowledge of pathologies related to hemostasis. In conclusion, the candidate will learn exceptional skills outside the area of his primary expertise in order to become an essential link between clinical pathologies and structural biology. Environment. The University of Washington has a strong track record of strength in both computational protein structure analysis and in hemostasis and thrombosis research. During the transition to an independent position the candidate will be mentored by Dr. Thomas, Dr. Pfaendtner and Dr. Lopez. He will also collaborate with various other faculties like Dr. Nathan White and Dr. Xiaoyun Fu. Dr. Thomas will provide him with the necessary computational and experimental equipment and office space also after his transition to independence. The computations will be run mainly on national supercomputing resources while the experiments will be performed in the laboratory of Dr. Thomas or in the laboratories of collaborating faculties. Description. Hemostasis is an essential mechanism to prevent blood loss from a damaged vessel. It is a complicated pathway that can become out of balance and lead for example to the formation of life threatening thrombi. Inflammation leads to the production of oxidizing agents. It has been reported in the literature that oxidation alters the structure of fibrin clot and influences the function of von Wille- brand Factor. However, it is currently not understood how the molecular structure of fibrin molecules and domains of von Willebrand Factor is altered due to oxidation in order to explain the experimentally observed functional modifications. The research proposed here investigates the link between altered fibrin clot structure and structural changes in single fibrin molecules, and the altered function of von Willebrand Factor as the result of oxidation. For this purpose, a combination of molecular dynamics simulations and flow chamber experiments will be used. Understanding the function of VWF and the process of fibrin polymerization under oxidizing conditions will help the design of therapeutics that can be administered to patients who are at risk of thrombosis due to inflammation.
描述(由申请人提供):候选人的长期职业目标是研究止血的结构基础以及外部因素如何改变止血。在K25奖期间,他将分析氧化作用如何改变止血过程中两种关键蛋白质的结构和功能,von Willebrand因子和纤维蛋白。候选人将使用分子动力学模拟,他的主要专长,以研究氧化如何改变蛋白质的结构稳定性。加速分子动力学方法专家Jim Pfaendtner博士将担任共同导师。模拟将通过显微镜实验补充,候选人将学习如何在温迪托马斯博士的指导下表现自己。感谢Jose洛佩斯博士作为共同导师,候选人将获得与止血相关的病理学的深入知识。总之,候选人将学习他的主要专业领域之外的特殊技能,以成为临床病理学和结构生物学之间的重要联系。环境华盛顿大学在计算蛋白质结构分析以及止血和血栓形成研究方面都有很强的实力。在向独立职位过渡期间,候选人将由托马斯博士、Pfaendtner博士和洛佩斯博士指导。他还将与Nathan白色博士和Xiaoyun Fu博士等其他学院合作。在他过渡到独立后,托马斯博士也将为他提供必要的计算和实验设备以及办公空间。计算将主要在国家超级计算资源上运行,而实验将在托马斯博士的实验室或合作学院的实验室进行。说明.止血是防止受损血管失血的基本机制。这是一个复杂的途径,可能会失去平衡,导致例如形成危及生命的血栓。炎症导致氧化剂的产生。据文献报道,氧化改变了纤维蛋白凝块的结构,影响了血管性血友病因子的功能。然而,目前尚不清楚纤维蛋白分子和血管性血友病因子结构域的分子结构如何因氧化而改变,以解释实验观察到的功能修饰。本文提出的研究探讨了纤维蛋白凝块结构改变与单个纤维蛋白分子结构变化之间的联系,以及氧化导致的血管性血友病因子功能改变。为此,将使用分子动力学模拟和流动室实验的组合。了解VWF的功能和氧化条件下纤维蛋白聚合的过程将有助于设计可用于因炎症而有血栓形成风险的患者的治疗方法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Gianluca Interlandi其他文献
Gianluca Interlandi的其他文献
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{{ truncateString('Gianluca Interlandi', 18)}}的其他基金
Differential targeting of von Willebrand factor depending on oxidizing conditions
根据氧化条件对冯维勒布兰德因子进行差异化靶向
- 批准号:
10474452 - 财政年份:2021
- 资助金额:
$ 14.36万 - 项目类别:
Differential targeting of von Willebrand factor depending on oxidizing conditions
根据氧化条件对冯维勒布兰德因子进行差异化靶向
- 批准号:
10296085 - 财政年份:2021
- 资助金额:
$ 14.36万 - 项目类别:
Differential targeting of von Willebrand factor depending on oxidizing conditions
根据氧化条件对冯维勒布兰德因子进行差异化靶向
- 批准号:
10649714 - 财政年份:2021
- 资助金额:
$ 14.36万 - 项目类别:
Structural analysis of oxidation effects on the hemostatic process
氧化对止血过程影响的结构分析
- 批准号:
9087315 - 财政年份:2013
- 资助金额:
$ 14.36万 - 项目类别:
Structural analysis of oxidation effects on the hemostatic process
氧化对止血过程影响的结构分析
- 批准号:
8486261 - 财政年份:2013
- 资助金额:
$ 14.36万 - 项目类别:
Structural analysis of oxidation effects on the hemostatic process
氧化对止血过程影响的结构分析
- 批准号:
9298695 - 财政年份:2013
- 资助金额:
$ 14.36万 - 项目类别:
Structural analysis of oxidation effects on the hemostatic process
氧化对止血过程影响的结构分析
- 批准号:
8880271 - 财政年份:2013
- 资助金额:
$ 14.36万 - 项目类别:
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