Resubmission: Structure/Function Determinants of Puncture Wound Thrombus Formation
Resubmission: Structure/Function Determinants of Puncture Wound Thrombus Formation
批准号:
10299372
负责人:
Brian Storrie
金额:
$62.08万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-09-01 至 2025-05-31
关键词:
3-DimensionalAccidentsAchievementAdhesivesAffectAlpha GranuleAntiplatelet DrugsArteriesAspirinAutocrine CommunicationBlood Coagulation FactorBlood PlateletsBlood VesselsCaliberCardiovascular systemCartoonsCoagulation ProcessCollagen ReceptorsCytoplasmic GranulesDataDefectDepositionDisease susceptibilityDoseDrug ModulationDrug TargetingEmbolismEventExperimental ModelsFibrinFibrinogen ReceptorsFutureGoalsGrowthHealthHemorrhageHemostatic functionHermanski-Pudlak SyndromeHumanIndividualKnowledgeLifeLightMaintenanceMedicalMedicineMicroscopyModelingMolecularMorphologyMusOperative Surgical ProceduresOrangesOutcomePatientsPatternPharmaceutical PreparationsPharmacotherapyPhysiologicalPlatelet ActivationPredictive ValueProcessPuncture biopsyPuncture procedurePuncture woundReceptor SignalingReproducibilityResearchResourcesRiskRoleSNAP receptorSignal TransductionSiteStratificationStructureStructure of jugular veinSyndromeSystemTestingThrombinThrombosisThromboxanesThrombusTimeTraumatic injuryVAMP-2Vascular SystemVenousVisualizationWound modelsadhesion receptorarterioleautocrinebaseclopidogrelcomparativedriving forcedrug actionexperimental studygenetic manipulationhazardinhibitor/antagonistmouse geneticsmutantnoveloligomycin sensitivity-conferring proteinpredictive modelingpublic health relevancereceptorresponseside effecttraumatic eventvenulevon Willebrand factor receptorwound
中文摘要
项目概要/摘要
科学假设和先前的研究:穿刺伤口,无论是意外,故意或医疗造成的
实践,例如,手术,可以是一个常规的重大创伤事件。此外,药物加重出血是主要的
目前的抗血小板药物的局限性,形成了心血管患者治疗的基石,
任何手术的主要责任。我们认为,对血小板中心反应的详细结构理解
在实际穿刺孔内发生的这些变化对于填补先前研究中的空白并产生重要的
框架的管理创伤性损伤和常见的出血副作用。
知识上的差距:以前的血栓形成方法主要集中在以下方面的例子:
暴露的血管基质保持完整,因此很少或没有出血发生,
由于2 P显微镜或SEM无法在单个血小板水平上评估血小板活化。
从这个受限制的实验角度来看,血栓结构的“核和壳”模型,即,一
锚定基质的水平核心、高度活化的血小板被弱活化血小板的外壳覆盖,
核心内的信号传导是凝血酶依赖性的,而壳内的信号传导是ADP/血栓素依赖性的
出现了我们认为,这一模型在实际出血中的应用可能受到限制,
伤口是一个开放的穿刺孔。
问题的解决方案:采用替代的可视化方法来确定个体的激活状态
血小板在3D空间,我们的初步研究已经产生了数据重新定义正常,出血停止
如在穿刺伤口模型中举例说明的。我们的数据揭示了一种空间分散的血小板活化模式,
血栓形成的初始步骤依赖于血小板聚集体的捕获
从外面盖住洞而不是填满洞。这促使我们制定了一个新的“上限和建设”
范例血小板中心和凝血因子级联事件如何整合在
范式现在是一个重要的问题。为了通过实验来理解这些多重输入,我们
提出的目标,首先集中在信号事件,无论是自分泌(血小板分泌,具体目标1)或
外分泌(根据抗血小板药物或DOAC的作用推断,具体目标2)以及
血小板粘附受体(特异性目标3)。我们还建议测试如何以及上限和建设范式
适用于较小的创伤。
英文摘要
PROJECT SUMMARY/ABSTRACT
Scientific Premise and Prior Research: Puncture wounds, be they produced by accident, intent or medical
practice, e.g., surgery, can be a routine to major traumatic event. Moreover, drug aggravated bleeding is a major
limitation of current antiplatelet drugs that form a cornerstone of cardiovascular patient therapy and a potentially
major liability to any surgery. We contend that detailed structure understanding of the platelet centric responses
that occur within the actual puncture hole is essential to fill a void in prior research and yield an important
framework for the management traumatic injuries and common bleeding side effects.
Gap(s) in knowledge: Previous approaches to thrombus formation have focused mostly on examples in
which the exposed vascular matrix remains intact and therefore little to no bleeding occurs and have suffered
from the inability of 2P microscopy or SEM to assess platelet activation at the level of individual platelets.
From this circumscribed experimental perspective, a “Core and Shell” model of thrombus structure, i.e., a
horizontal core of matrix anchored, highly activated platelets covered by a shell of weakly activated platelets in
which signaling within the Core is thrombin-dependent and within the Shell is ADP/thromboxane-dependent
has emerged. We submit that this model may well be limited in its application to actual bleeding where the
wound is an open puncture hole.
Solution to problem: Taking alternate visualization approaches that determine the activation state of individual
platelets in 3D space, our Preliminary Studies have already yielded data redefining normal, bleeding cessation
as exemplified in a puncture wound model. Our data reveal a spatially dispersed, platelet activation pattern and
strong indications that initial steps in thrombus formation are dependent on the capture of platelet aggregates
that cap the hole from the outside rather than fill the hole. This has led us to formulate a new “Cap and Build”
paradigm. How both platelet-centric and coagulation factor cascade events can be integrated within the
paradigm is now an important question. To understand these multiple inputs through experimentation, we have
proposed Aims that focus first on signaling events, be they autocrine (platelet secretion, Specific Aim 1) or
exocrine (as inferred from the effects of anti-platelet drugs or DOACs, Specific Aim 2), and the importance of
platelet adhesion receptors (Specific Aim 3). We also propose to test how well the Cap and Build paradigm
apply to smaller, less traumatic injury.
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会议论文
Resubmission: Structure/Function Determinants of Puncture Wound Thrombus Formation
-
批准号:10625508
-
项目类别:
-
资助金额:$64.03万
-
财政年份:2021
-
负责人:Brian Storrie
-
依托单位:
Structure/Function Determinants of Platelet Granule Secretion
-
批准号:8707849
-
项目类别:
-
资助金额:$36.49万
-
财政年份:2013
-
负责人:Brian Storrie
-
依托单位:
Structure/Function Determinants of Platelet Granule Secretion
-
批准号:8852178
-
项目类别:
-
资助金额:$36.37万
-
财政年份:2013
-
负责人:Brian Storrie
-
依托单位:
Structure/Function Determinants of Platelet Granule Secretion
-
批准号:8562359
-
项目类别:
-
资助金额:$33.28万
-
财政年份:2013
-
负责人:Brian Storrie
-
依托单位:
Structure/Function Determinants of Platelet Granule Secretion
-
批准号:9068338
-
项目类别:
-
资助金额:$36.89万
-
财政年份:2013
-
负责人:Brian Storrie
-
依托单位:
Role of Rab Proteins in Golgi Apparatus Structure and Function
-
批准号:8537212
-
项目类别:
-
资助金额:$31.52万
-
财政年份:2011
-
负责人:Brian Storrie
-
依托单位:
Role of Rab Proteins in Golgi Apparatus Structure and Function
-
批准号:8661822
-
项目类别:
-
资助金额:$0.81万
-
财政年份:2011
-
负责人:Brian Storrie
-
依托单位:
Role of Rab Proteins in Golgi Apparatus Structure and Function
-
批准号:8040313
-
项目类别:
-
资助金额:$26.88万
-
财政年份:2011
-
负责人:Brian Storrie
-
依托单位:
Role of Rab Proteins in Golgi Apparatus Structure and Function
-
批准号:8723844
-
项目类别:
-
资助金额:$31.84万
-
财政年份:2011
-
负责人:Brian Storrie
-
依托单位:
Role of Rab Proteins in Golgi Apparatus Structure and Function
-
批准号:8334628
-
项目类别:
-
资助金额:$27.55万
-
财政年份:2011
-
负责人:Brian Storrie
-
依托单位:
CORRELATIVE MICROSCOPY OF GOLGI APPARATUS ASSEMBLY
-
批准号:7358059
-
项目类别:
-
资助金额:$0.2万
-
财政年份:2006
-
负责人:Brian Storrie
-
依托单位:
CORRELATIVE MICROSCOPY OF GOLGI APPARATUS ASSEMBLY
-
批准号:7181356
-
项目类别:
-
资助金额:$0.22万
-
财政年份:2005
-
负责人:Brian Storrie
-
依托单位:
CORRELATIVE MICROSCOPY OF GOLGI APPARATUS ASSEMBLY
-
批准号:6975379
-
项目类别:
-
资助金额:$1.8万
-
财政年份:2004
-
负责人:Brian Storrie
-
依托单位:
Mechanisms of Golgi Apparatus Protein Recycling
-
批准号:6458820
-
项目类别:
-
资助金额:$17.45万
-
财政年份:2002
-
负责人:Brian Storrie
-
依托单位:
Mechanisms of Golgi Apparatus Protein Recycling
-
批准号:6622884
-
项目类别:
-
资助金额:$15.95万
-
财政年份:2002
-
负责人:Brian Storrie
-
依托单位:
Mechanisms of Golgi Apparatus Protein Recycling
-
批准号:6729980
-
项目类别:
-
资助金额:$26.75万
-
财政年份:2002
-
负责人:Brian Storrie
-
依托单位:
Mechanisms of Golgi Apparatus Protein Recycling
-
批准号:6643788
-
项目类别:
-
资助金额:$7.38万
-
财政年份:2002
-
负责人:Brian Storrie
-
依托单位:
Mechanisms of Golgi Apparatus Protein Recycling
-
批准号:6845569
-
项目类别:
-
资助金额:$12.76万
-
财政年份:2002
-
负责人:Brian Storrie
-
依托单位:
STRUCTURAL ORGANIZATION OF THE MAMMALIAN GOLGI COMPLEX
-
批准号:2641764
-
项目类别:
-
资助金额:$4.54万
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财政年份:1998
-
负责人:Brian Storrie
-
依托单位:
PROTEIN RETENTION IN THE MAMMALIAN GOLGI APPARATUS
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批准号:3023415
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项目类别:
-
资助金额:$3.25万
-
财政年份:1992
-
负责人:Brian Storrie
-
依托单位:
海外基金