ASK1 a novel regulator of platelet function
ASK1 一种新型血小板功能调节剂
基本信息
- 批准号:9899282
- 负责人:
- 金额:$ 47.7万
- 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:2019-04-01 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAdhesionsAffectAgonistAntiplatelet DrugsApolipoprotein EApoptosisArterial Fatty StreakArteriesAtherosclerosisBleeding time procedureBlood PlateletsBrainCardiovascular DiseasesCessation of lifeCoagulation ProcessCoronaryCoronary heart diseaseDataDevelopmentDiseaseDoseDrug KineticsEvaluationFamilyFamily memberGeneticGrowthHeartHemostatic functionHigh Fat DietHumanHyperlipidemiaIn VitroIntegrinsInterventionIschemiaIschemic StrokeLasersMAP Kinase GeneMAP Kinase Kinase KinaseMAP3K5 geneMiddle Cerebral Artery OcclusionMitogen-Activated Protein KinasesModelingMusMyocardial InfarctionObesityObstructionPathogenesisPathway interactionsPharmacodynamicsPhase III Clinical TrialsPhenotypePhosphotransferasesPhysiologicalPlasmaPlatelet ActivationPlatelet aggregationPlayPublishingReperfusion InjuryReperfusion TherapyRoleRuptureScienceSignal TransductionSignaling MoleculeSiteSpecificityStrokeStructureTailTestingTherapeuticTherapeutic InterventionThrombosisThrombusToxic effectatherogenesisatherosclerotic plaque ruptureatherothrombosisbasecardiovascular disorder therapycerebral arterycombatendothelial dysfunctionin vivoin vivo Modelinhibitor/antagonistinnovationkinase inhibitormembermouse modelnonalcoholic steatohepatitisnoveloxidized low density lipoproteinplatelet functionprotective effectreceptorresponsesmall molecule inhibitorsmall molecule librariesstroke modelvascular injuryvirtual
项目摘要
Cardiovascular disease (CVD) is the number one killer of mankind. Most CVDs are associated
with atherosclerosis and thrombosis. Mounting evidence suggests that platelets are the initiators
of both atherosclerosis and thrombosis. Agonist stimulation in platelets is known to activate
MAPKs, and it has been shown that they are important for platelet activities both in vivo and in
vitro. Despite this evident role of MAPK signaling contributing to platelet functions, the
mechanisms through which they regulate platelet activities are not fully understood. We have
identified that a member of the MAP3K family, apoptosis signal-regulating kinase (ASK1) is
present in both human and murine platelets and is activated by physiological agonists. We have
shown that Ask1 activity supports platelet aggregation and secretion, and ablation of Ask1
confers a protective effect in in vivo models of thrombosis. We therefore hypothesize that
platelet ASK1 is a key regulator of atherogenesis, atherothrombosis, and ischemia
reperfusion (I/R) injury resulting from clot dissolution in MI, and stroke. We have also
identified several structurally distinct ASK1 inhibitors based on information from published virtual
chemical library screens. Two of these compounds have shown excellent efficacy in protecting
mice from thrombosis with minimal effects on hemostasis, as assessed by tail bleeding time and
laser-induced hemostasis model. This R01 proposal is focused on delineating the role of platelet
ASK1 in initiating atherogenesis, atherothrombosis, and aggravating I/R injury. Accordingly,
three Specific Aims have been proposed. Specific Aim 1 will test the hypothesis that platelet
ASK1 is key in initiating atherogenesis. We will use a hyperlipidemia mouse model (Apoe-/- mice
fed with high-fat diet) to study the effect of ablation or inhibition of platelet Ask1 on plaque
formation. Specific Aim 2 will test the hypothesis that platelet ASK1 is a central regulator of
platelet activation during atherosclerotic plaque rupture (atherothrombosis). We will use an
innovative mouse model to mimic thrombus formation at the site of plaque rupture. Specific
Aim 3 will test the hypothesis that platelet ASK1 is responsible for aggravating I/R injury. We
will use the transient middle cerebral artery occlusion model (tMCAO) of stroke to assess the
effect of ablation/inhibition of platelet ASK1 on I/R injury. Successful completion of this proposal
will help to develop a number of therapeutic interventions for thrombosis associated diseases
such as atherosclerosis, MI, and stroke.
心血管疾病(CVD)是人类的第一杀手。大多数 CVD 都与
伴有动脉粥样硬化和血栓形成。越来越多的证据表明血小板是引发者
动脉粥样硬化和血栓形成。已知激动剂刺激血小板可激活
MAPKs,并且已经表明它们对于体内和体内的血小板活性都很重要
体外。尽管 MAPK 信号传导对血小板功能具有明显的作用,但
它们调节血小板活性的机制尚不完全清楚。我们有
确定 MAP3K 家族的成员凋亡信号调节激酶 (ASK1)
存在于人和鼠血小板中并被生理激动剂激活。我们有
显示 Ask1 活性支持血小板聚集和分泌,以及 Ask1 的消融
在体内血栓形成模型中具有保护作用。因此我们假设
血小板 ASK1 是动脉粥样硬化形成、动脉粥样硬化血栓形成和缺血的关键调节因子
心肌梗死和中风中血栓溶解导致的再灌注 (I/R) 损伤。我们还有
根据已发布的虚拟信息,确定了几种结构不同的 ASK1 抑制剂
化学库屏幕。其中两种化合物在保护方面表现出优异的功效
通过尾部出血时间和评估,小鼠免受血栓形成对止血的影响最小
激光诱导止血模型。该 R01 提案的重点是描述血小板的作用
ASK1 启动动脉粥样硬化、动脉粥样硬化血栓形成和加重 I/R 损伤。因此,
提出了三项具体目标。具体目标 1 将检验以下假设:血小板
ASK1 是启动动脉粥样硬化形成的关键。我们将使用高脂血症小鼠模型(Apoe-/- 小鼠
高脂饮食喂养)研究血小板Ask1的消融或抑制对斑块的影响
形成。具体目标 2 将检验以下假设:血小板 ASK1 是
动脉粥样硬化斑块破裂(动脉粥样硬化血栓形成)期间血小板活化。我们将使用一个
创新小鼠模型模拟斑块破裂部位的血栓形成。具体的
目标 3 将检验血小板 ASK1 导致 I/R 损伤加重的假设。我们
将使用中风的短暂性大脑中动脉闭塞模型(tMCAO)来评估
血小板 ASK1 的消融/抑制对 I/R 损伤的影响。顺利完成本提案
将有助于开发一些针对血栓相关疾病的治疗干预措施
例如动脉粥样硬化、心肌梗死和中风。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ULHAS P NAIK其他文献
ULHAS P NAIK的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('ULHAS P NAIK', 18)}}的其他基金
ASK1 a novel regulator of platelet function
ASK1 一种新型血小板功能调节剂
- 批准号:
10383745 - 财政年份:2019
- 资助金额:
$ 47.7万 - 项目类别:
Regulation of Platelet Reactivity by S1P Signaling
S1P 信号传导调节血小板反应性
- 批准号:
10436813 - 财政年份:2019
- 资助金额:
$ 47.7万 - 项目类别:
Regulation of Platelet Reactivity by S1P Signaling
S1P 信号传导调节血小板反应性
- 批准号:
10183303 - 财政年份:2019
- 资助金额:
$ 47.7万 - 项目类别:
相似国自然基金
动脉粥样硬化发生中CAPN2影响内皮粘连的机制研究
- 批准号:82000254
- 批准年份:2020
- 资助金额:24 万元
- 项目类别:青年科学基金项目
层粘连蛋白受体第272位苏氨酸影响猪瘟病毒感染的分子机制
- 批准号:31902264
- 批准年份:2019
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
层粘连蛋白调控巨噬细胞和脂肪基质细胞影响肥胖脂肪组织重塑的机制
- 批准号:
- 批准年份:2019
- 资助金额:300 万元
- 项目类别:
保留双层肌膜的功能性肌肉移植中S1P/S1PR1轴调节巨噬细胞迁移及分化对移植肌肉粘连与功能的影响
- 批准号:81871787
- 批准年份:2018
- 资助金额:55.0 万元
- 项目类别:面上项目
大黄-桃仁介导AhR通路影响Th17/Treg和肠道菌群平衡改善肠粘膜屏障功能防治粘连性肠梗阻的机制研究
- 批准号:81804098
- 批准年份:2018
- 资助金额:21.0 万元
- 项目类别:青年科学基金项目
相似海外基金
Resident Memory T cells in Chronic Kidney Disease
慢性肾脏病中的常驻记忆 T 细胞
- 批准号:
10676628 - 财政年份:2023
- 资助金额:
$ 47.7万 - 项目类别:
Endothelial-Leukocyte Adhesion in CAR T Cell Treatment Associated Neurotoxicity
CAR T 细胞治疗相关神经毒性中的内皮-白细胞粘附
- 批准号:
10735681 - 财政年份:2023
- 资助金额:
$ 47.7万 - 项目类别:
THE ROLE OF MESENCHYMAL PROGENITOR CELLS IN ABNORMAL UTERINE REPAIR
间充质祖细胞在异常子宫修复中的作用
- 批准号:
10660189 - 财政年份:2023
- 资助金额:
$ 47.7万 - 项目类别:
Analyzing the role of cAMP and STAT3 signaling in cartilage homeostasis and osteoarthritis development
分析 cAMP 和 STAT3 信号在软骨稳态和骨关节炎发展中的作用
- 批准号:
10822167 - 财政年份:2023
- 资助金额:
$ 47.7万 - 项目类别:
Mechanotransduction via LIM Domain Protein Mechanosensing
通过 LIM 结构域蛋白机械传感进行机械转导
- 批准号:
10735689 - 财政年份:2023
- 资助金额:
$ 47.7万 - 项目类别: