Pathway maps of platelet phenotype and function

血小板表型和功能的通路图

基本信息

批准号：
10599257
负责人：
JOSEPH E ASLAN
金额：
$ 38.5万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599257
关键词：
Acceleration Address Adhesions Adhesives Affect Agonist Alpha Granule Atherosclerosis Biochemical Biological Blood Cells Blood Platelets Cardiovascular Diseases Cause of Death Cell model Cell-Cell Adhesion Cells Chronic Disease Coagulation Process Complement Complex Cues Cytokine Receptors Cytoplasmic Granules Cytoskeleton Data Disease Endothelium Event Filopodia Glycoproteins Goals Hemorrhage Hemostatic Agents Hemostatic function Image Inflammation Inflammatory Inflammatory Response Injury Integrins Knowledge Leukocytes Maps Measurement Measures Mediating Mediator Methodology Methods Modeling Molecular Morbidity - disease rate Output P-Selectin Pathogenesis Pathway interactions Phenotype Phospholipase Phosphorylation Physiological Platelet Activation Process Proteins Proteomics Public Health Purinoceptor Receptor Signaling Regulation Role Signal Pathway Signal Transduction Site Specific qualifier value System Systems Biology Testing Thrombosis Work adhesion receptor disability extracellular improved in vivo mortality novel platelet function platelet phenotype prevent programs receptor release factor response thrombotic tool trafficking translatable strategy vascular inflammation

项目摘要

PROJECT SUMMARY As the primary cellular mediators of hemostasis, platelets are optimized to limit bleeding through rapid adhesion, secretion and aggregation responses at sites of endothelial injury. Platelets also adhere to dysfunctional endothelium, where they secrete proinflammatory molecules and form aggregates with leukocytes to progress vascular inflammation in a manner relevant to the pathogenesis of chronic diseases, including atherosclerosis. Ongoing efforts aiming to understand and target platelet activities specific to disease have characterized a spectrum of platelet functional phenotypes associated with inflammatory, thrombotic and other conditions. Despite the identification of key molecular alterations that highlight differences between these phenotypes, it remains unclear how different platelet phenotypes develop, how they should be defined, and, ultimately, how they should be targeted. We hypothesize that platelet hemostatic, inflammatory and other phenotypes are determined by the systematic activation of intracellular signaling pathways and effectors that result in specific platelet functional outputs in response to physiological context. We aim to systematically define intracellular signaling events that progress platelet adhesion (Aim 1), secretion (Aim 2) and aggregation (Aim 3) in hemostatic programs and to determine how these responses mechanistically differ in the context of vascular inflammation. We will engage these studies through the use of a high-throughput, proteomics-based workflow that measures and maps intracellular signaling events and pathways underlying platelet function in specific experimental and physiological contexts. We now use this set of proteomics, computational and cell biological tools to build pathway maps intracellular signaling relations in platelet activation programs. In this proposal, we use this first-in-class pathway mapping methodology together with other physiological and systems biology tools to address how platelet signaling programs specify platelet phenotypes favoring hemostatic and inflammatory responses. Ultimately, this work will generate knowledge as well as a conceptual means to define and understand systems level mechanisms of platelet regulation in hemostasis as well as in inflammation and the manifestation of disease.

项目摘要作为止血的主要细胞介质，血小板被优化以限制通过快速出血内皮损伤部位的粘附，分泌和聚集反应。血小板也遵守功能失调的内皮，它们分泌促炎分子并与白细胞以与慢性疾病的发病机理相关的方式进行血管炎症，包括动脉粥样硬化。旨在理解和针对特定于疾病的血小板活动的持续努力已经表征了与炎症，血栓形成和其他条件。尽管鉴定了关键分子改变，这些变化突出了这些之间的差异表型，尚不清楚如何形成不同的血小板表型，应如何定义它们以及，以及最终，应如何将它们作为目标。我们假设血小板止血，炎症和其他表型是由细胞内信号通路和效应子的系统激活确定的响应生理环境，导致特定的血小板功能输出。我们的目标是系统地定义会进展血小板粘附的细胞内信号传导事件（AIM 1），分泌（AIM 2）和聚集（目标3）在止血程序中，并确定这些反应在机械上如何在机械上差异血管炎症。我们将通过使用高通量，基于蛋白质组学的研究来参与这些研究测量和绘制细胞内信号传导事件和途径血小板功能的工作流程特定的实验和生理环境。现在，我们使用这组蛋白质组学，计算和细胞构建途径的生物工具映射血小板激活程序中的细胞内信号传导关系。在这个提案，我们将此一流的途径映射方法以及其他生理和系统生物学工具以解决血小板信号程序如何指定血小板表型有利的止血和炎症反应。最终，这项工作将产生知识和概念定义和理解止血和血小板调节的系统水平机制以及炎症和疾病的表现。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Platelet reactivity and platelet count in women with iron deficiency treated with intravenous iron.

DOI：
10.1002/rth2.12692
发表时间：
2022-03
期刊：
Research and practice in thrombosis and haemostasis
影响因子：
4.6
作者：
Elstrott BK;Lakshmanan HHS;Melrose AR;Jordan KR;Martens KL;Yang CJ;Peterson DF;McMurry HS;Lavasseur C;Lo JO;Olson SR;DeLoughery TG;Aslan JE;Shatzel JJ
通讯作者：
Shatzel JJ

Analyzing causal relationships in proteomic profiles using CausalPath.

DOI：
10.1016/j.xpro.2021.100955
发表时间：
2021-12-17
期刊：
STAR protocols
影响因子：
0
作者：
Luna A;Siper MC;Korkut A;Durupinar F;Dogrusoz U;Aslan JE;Sander C;Demir E;Babur O
通讯作者：
Babur O

Fibrin reaches out to GPVI to influence how platelets shape clots.

纤维蛋白接触 GPVI 来影响血小板形成血栓的方式。

DOI：
10.1016/j.jtha.2022.11.027
发表时间：
2023
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
0
作者：
Aslan,JosephE
通讯作者：
Aslan,JosephE

Causal interactions from proteomic profiles: Molecular data meet pathway knowledge.

DOI：
10.1016/j.patter.2021.100257
发表时间：
2021-06-11
期刊：
Patterns (New York, N.Y.)
影响因子：
0
作者：
Babur Ö;Luna A;Korkut A;Durupinar F;Siper MC;Dogrusoz U;Vaca Jacome AS;Peckner R;Christianson KE;Jaffe JD;Spellman PT;Aslan JE;Sander C;Demir E
通讯作者：
Demir E

Novel disintegrin-like peptides derived from an amphibian skin cDNA sequence of Hypsiboas punctatus.

源自 Hypsiboas punctatus 两栖动物皮肤 cDNA 序列的新型解整合素样肽。

DOI：
10.1002/psc.3382
发表时间：
2022
期刊：
Journal of peptide science : an official publication of the European Peptide Society
影响因子：
0
作者：
Pires,DiegoAT;Tacca,LuisaMRA;Aslan,JosephE;Murad,AndréM;Nascimento,ClaudiaJ;Barbosa,EderA;BlochJr,Carlos
通讯作者：
BlochJr,Carlos