Identifying the function of the Fibrin(ogen) alpha-C connector region
确定纤维蛋白(原)α-C 连接器区域的功能
基本信息
- 批准号:9813281
- 负责人:
- 金额:$ 43.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAmino AcidsAreaAtomic Force MicroscopyBiochemistryBiological AssayBiophysicsBloodBlood PlateletsBlood coagulationBlood flowCardiovascular DiseasesCleaved cellCoagulation ProcessCrystallizationCytolysisDataDevelopmentDiagnosisDiffuseDigestionElasticityEngineeringEnzymesErythrocytesExhibitsFiberFibrinFibrinogenFibrinolysisFluorescence Resonance Energy TransferGoalsHemorrhageHemostatic functionHumanIndividualInjuryInterdisciplinary StudyIschemic StrokeKineticsLabelLengthLyticMeasuresMechanicsMediatingMedicineMolecularMolecular BiologyMolecular StructureMutationMyocardial InfarctionNomenclaturePathologyPatientsPeptide HydrolasesPermeabilityPhysicsPlasmaPlasminPlayPlug-inPolymersPredispositionProcessPropertyProtein EngineeringRecombinant ProteinsRecombinantsReportingResearchResearch PersonnelResearch Project GrantsRoleRubberScanning Electron MicroscopyScienceScientistSeriesSiteStretchingStrokeStructureStudentsTechnologyTestingThromboembolismThrombosisTrainingTurbidimetryUniversitiesVariantVenousWorkWound Healingbaseblood vessel occlusionclinical Diagnosiscrosslinkdensityexperienceexperimental studyfibrinopeptideflexibilityforestgraduate studentimprovedmechanical propertiesmolecular scalenetwork architecturenext generationpolymerizationpreventscaffoldsensorskillstherapy developmentundergraduate student
项目摘要
Project Summary/Abstract
The broad, long-term objective of the proposed research is to determine the mechanisms regulating
fibrin and fibrinogen function, with the goal of improving the diagnosis and treatment of cardiovascular
disease. In so doing, we plan to train the next generation of scientists with an interdisciplinary skill set
to tackle problems in medicine, physics, and biochemistry.
In this specific proposal, we will study the polymerization, mechanical properties, and enzymatic digestion of
fibrin fibers. Fibrin fibers form the structural scaffold for blood clots and are remarkably elastic, often being
compared to rubber bands, before being digested by plasmin after wound healing terminates. Understanding
how fibrin can act like a rubber is potentially important for both clinical diagnoses and the development of
treatment approaches for many cardiovascular diseases, because altered fibrin elasticity is often associated with
strokes, heart attacks, and other pathologies. However, we currently do not have a complete understanding of
which structural properties of fibrin enable its elasticity. Based on previous studies and indirect evidence, we
hypothesize that these elastic properties originate from a specific region in fibrin, the αC connector region. In
this research project, we will test this hypothesis and will also determine whether the αC connector region is
involved in fibrin polymerization, fibrin structure, and the digestion of fibrin by the enzyme plasmin. This
interdisciplinary work will rely heavily on student researchers, providing training in molecular biology,
biochemistry, biophysics, and blood coagulation.
Specific Aim 1: Determine the importance of the αC region on the mechanical and structural properties
of fibrin fibers and fibrin clots. Using protein engineering, we will generate fibrin molecules with truncated αC
connector regions. We will test the polymerization and structure of fibrin fibers composed of these molecules
using fibrinopeptide release assays, turbidity and turbidimetry, scanning electron microscopy, and permeability
assays and compare it to fibers made of native, human fibrin. We will measure the mechanical properties of
these fibers using atomic force microscopy. Additionally, we will engineer fibrin molecules with molecular tension
sensors (based on Fӧrster Resonance Energy Transfer) embedded in the αC connector region. Taken together,
these experiments will reveal the extent to which this region regulates fibrin polymerization, mechanical
properties, and fiber structure.
Specific Aim 2: Determine the mechanical and structural regulators of fibrin fiber fibrinolytic rates. Little
is known about how the mechanical and structural properties of individual fibers influence their susceptibility to
plasmin lysis, even though the lysis of a blood clot occurs through the digestion of fibers. We will determine how
internal fiber structure, fiber tension, and the spacing between fibers impacts plasmin digestion using native fibrin
and the engineered fibrin molecules described in Aim 1.
项目摘要/摘要
拟议研究的广泛、长期目标是确定调控机制
纤维蛋白和纤维蛋白原功能,目的是改善心血管疾病的诊断和治疗
疾病。通过这样做,我们计划培养具有跨学科技能的下一代科学家
解决医学、物理和生物化学方面的问题。
在这个具体的提案中,我们将研究聚合体、机械性能和酶消化
纤维蛋白纤维。纤维蛋白纤维构成了血栓的结构支架,具有显著的弹性,通常是
与橡皮筋相比,在伤口愈合终止后被纤溶酶消化之前。理解
纤维蛋白如何像橡胶一样发挥作用对临床诊断和糖尿病的发展都具有潜在的重要意义。
许多心血管疾病的治疗方法,因为纤维蛋白弹性改变通常与
中风、心脏病发作和其他病症。但是,我们目前对此还没有完全的了解。
纤维蛋白的哪些结构特性使其具有弹性。基于之前的研究和间接证据,我们
假设这些弹性性质起源于纤维蛋白中的特定区域,即αC连接器区域。在……里面
在这个研究项目中,我们将检验这一假设,并还将确定αC连接区是否
参与纤维蛋白聚合、纤维蛋白结构以及纤溶酶对纤维蛋白的消化。这
跨学科工作将在很大程度上依赖于学生研究人员,提供分子生物学方面的培训,
生物化学、生物物理学和血液凝固。
具体目标1:确定αC区对机械和结构性能的重要性
纤维蛋白纤维和纤维蛋白凝块。利用蛋白质工程,我们将产生截短αC的纤维蛋白分子
连接线区域。我们将测试由这些分子组成的纤维蛋白纤维的聚合和结构
使用纤维蛋白肽释放分析、浊度和浊度法、扫描电子显微镜和通透性
对它进行分析,并与由天然人类纤维蛋白制成的纤维进行比较。我们将测量材料的力学性能
这些纤维使用原子力显微镜。此外,我们还将设计具有分子张力的纤维蛋白分子
嵌入在ӧC连接器区域的传感器(基于FαRster共振能量转移)。加在一起,
这些实验将揭示该区域在多大程度上调节纤维蛋白聚合,机械
性能和纤维结构。
具体目标2:确定纤维蛋白纤维纤溶率的机械和结构调节因素。一点儿
已知单个纤维的机械和结构特性如何影响它们对
纤溶酶溶解,即使血液凝块的溶解是通过纤维的消化发生的。我们将决定如何
纤维内部结构、纤维张力和纤维间距影响使用天然纤维蛋白的纤溶酶消化
和目标1中描述的工程纤维蛋白分子。
项目成果
期刊论文数量(0)
专著数量(0)
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