公共卫生的相关性

项目说明血栓形成是重大疾病,如中风,败血症和心脏发作的一个致命的并发症。除了阿司匹林,血栓形成的预防/治疗目前服用的药物主要集中于血小板P2Y12受体与氯吡格雷作为常规临床使用拮抗剂。然而,氯吡格雷已经表现出性能不稳定,要么无法避免血栓形成或引起出血。该项目的长期目标是建立非血小板P2Y受体,例如P2Y2受体(P2Y2R),作为新的分子靶标,其控制炎症诱导的血管血栓形成。虽然公认,组织因子(TF)是血栓形成的引发剂,很少上P2Y受体在各种炎性刺激物诱导的TF表达调控的贡献是已知的。这是一个重要的问题,因为许多促炎性刺激促进细胞核苷酸释放和灭活ectonucleotidases,导致细胞外核苷酸,其反过来AMPLIFY原受体经由P2Y受体共激活信令的积累。所述PI先前报道,P2Y2R被上调在搭支架的冠状动脉,它是在人冠状动脉内皮细胞(HCAEC)所有P2Y受体的主要亚型。他们还报道P2Y2R的活化显着诱导TF表达和活性HCAEC。这些PI的初步研究表明,TF诱导P2Y2R也适用于人原代单核细胞的血液和体内小鼠冠状动脉内皮,它涉及转录和转录后机制。 Further, LPS-induced TF induction is significantly decreased when extracellular nucleotides are removed by apyrase, and importantly, P2Y2R-null mice are protected from endotoxic death. Based on these original findings, the PI proposes the hypothesis: The non-platelet P2Y2R is a previously unrecognized key mediator in inflammation-induced thrombosis via TF induction. This hypothesis will be tested by the pursuit of three specific aims: 1) Determine the transcriptional mechanism underlying P2Y2R activation of the TF gene in vascular endothelial cells and blood monocytes; 2) Define the post-transcriptional mechanism by which P2Y2R activation leads to increased TF mRNA stability in vascular endothelial cells and blood monocytes; 3) Assess the role of P2Y2R/TF axis in mouse models of inflammation-induced thrombosis. Aim 1 will determine the role of a new AP-1 binding site with new AP-1 components Fra-1/ATF2 in TF mRNA induction by P2Y2R. Aim 2 will determine the roles of the AU-rich elements in TF 3'UTR along with their binding proteins and the miRNA mechanisms contribute to P2Y2R-mediated TF mRNA stabilization. Aim 3 will verify if deletion of P2Y2R prevents LPS-induced disseminated intravascular coagulation and reduces atherothrombosis. The proposed study will be performed in primary cultured human cells and cells isolated from P2Y2R-null mice, followed by a series of in vivo studies. The proposed research is significant, because it is expected to advance and expand understanding of how inflammation leads to increased thrombogenicity of blood vessels via the new P2Y2R-TF axis. Ultimately, such knowledge has the potential to produce new strategies in combating thrombogenic diseases.

机构
国家卫生研究所(NIH)
研究所
国家心肺血液研究所(NHLBI)
类型
研究项目(R01)
项目#
5 r01hl125279-04
应用#
9843159
研究部门
心血管系统研究组(AICS)动脉粥样硬化与炎症
项目官员
Ochocinska,玛格丽特·J
项目开始
2017-01-01
项目结束
2021-11-30
预算开始
2019-12-01
预算结束
二○二○年十一月三十○日
支持一年
4
财政年度
2020
总成本
间接成本
的名字
奥本大学
部门
药理
类型
学校的药店
兔褐#
066470972
城市
奥本大学
艾尔
国家
美国
邮政编码
36849
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