权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The role of protease activated receptors on platelets

蛋白酶激活受体对血小板的作用

基本信息

批准号：
9889979
负责人：
Marvin Thomas Nieman
金额：
$ 31.7万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-15 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9889979
关键词：
Address Affect Agonist Alleles Allosteric Site Amides Amino Acids Antiplatelet Drugs Aspirin Binding Binding Sites Blood Platelets Blood Vessels Blood coagulation Cells Deuterium Development Dominant-Negative Mutation Effectiveness F2R gene FDA approved Family Frequencies G-Protein-Coupled Receptors Genetic Polymorphism Genotype Goals Hemorrhage Hemostatic function Heritability Histidine Homo Human Hybrids Hydrogen Hydroxyl Radical Individual Intracranial Hemorrhages Lead Ligand Binding Ligands Mass Spectrum Analysis Membrane Molecular Molecular Conformation Molecular Structure Monitor Myocardial Infarction Output Pathologic Pathway interactions Patients Pharmacogenomics Pharmacology Study Physiological Platelet Activation Platelet aggregation Population Proteinase-Activated Receptors Proteins Receptor Activation Receptor Signaling Recording of previous events Reporting Research Resistance Resolution Risk Role Signal Pathway Signal Transduction Single Nucleotide Polymorphism Stroke Structure Surface Techniques Testing Therapeutic Thrombin Thrombin Receptor Thrombus Treatment Protocols Variant acute coronary syndrome clopidogrel experience insight inter-individual variation interest molecular rearrangement new therapeutic target platelet function prevent public health relevance receptor receptor function response side effect standard of care structural biology therapeutic target therapy resistant

项目摘要

DESCRIPTION (provided by applicant): Platelets are defined by their essential roles in hemostasis and the formation of pathological thrombi. Therefore, the major focus of platelet research is focused on identifying and developing safer and more effective anti- thrombotic therapies. A second goal is to have the ability to predict the effectiveness of specific therapies across populations. Pharmacogenomics may allow us to predict who will respond to or be resistant to therapies. In order for this to be successful, there needs to be a clear relationship between specific polymorphisms and physiological output. Finally, the alleles need to be present at high enough frequency to warrant testing prior to the start of therapy. In the current project w will examine common polymorphisms of a platelet receptor (PAR4) to explain the differences in reactivities and response to an antagonist at the molecular level. We will determine the structural rearrangement of PAR4 upon activation by thrombin using structural mass spectrometry (amide hydrogen deuterium exchange (HDX), histidine HDX, and hydroxyl radical foot-printing) with purified PAR4 and PAR4 on cells and platelets. These studies will determine how the tethered ligand influences the overall conformation of the receptor. Pharmacological studies in human platelet show that the PAR4 sequence variants have dramatically different responses. For example, PAR4-120T is hyper-reactive and PAR4-296V is resistant to signaling. We will determine how the PAR4 variants affect the ligand binding site and the transition to the active conformation at the molecular level. Further, PAR4-296V suppresses the activity of other alleles suggesting that it forms dominant negative homodimers. We will examine the physical interaction between PAR4 variants, PAR1 and P2Y12 to determine how these receptors influence signaling pathways. Finally, we will determine how the PAR4 sequence variants influence platelet reactivity in acute coronary syndrome patients on the current standard of care (aspirin and a P2Y12 antagonist) and if the altered platelet reactivity due to PAR4 variants is exacerbated with the PAR1 antagonist vorapaxar. By analyzing the structural rearrangements of PAR4 following activation by thrombin, these studies will provide the first detailed description of the tethered ligand activation mechanism for the PAR family and have the potential to uncover allosteric sites that can be exploited therapeutically. More specifically, understanding how naturally occurring sequence variants influence PAR4's response may allow us to predict the most appropriate antiplatelet therapy for patients depending on their genotype.