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Biased PAR1 Agonism in Sickle Cell Disease

镰状细胞病中 PAR1 激动的偏向性

基本信息

批准号：
10097140
负责人：
Erica M Sparkenbaugh
金额：
$ 38.88万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-10 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10097140
关键词：
Affect Agonist Anti-Inflammatory Agents Anticoagulants Antiinflammatory Effect Attenuated Blood Platelets Blood Vessels Cardiovascular system Cell physiology Cells Cessation of life Chronic Coagulation Process Complex Data Disease Disease Management Endothelial Cells Endothelium Erythrocytes Etiology Functional disorder G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Generations Genes Genetic Goals Hemolytic Anemia Hospitalization Human Infection Inflammation Inflammatory Response Lead Long-Term Effects Longevity Mediating Mediator of activation protein Methods Mus Mutation Newborn Infant Nucleotides Organ Oxidative Stress PAR-1 Receptor Pain Pathology Patients Pharmaceutical Preparations Pharmacology Point Mutation Protease Inhibitor Publishing Reperfusion Injury Role Sickle Cell Sickle Cell Anemia Signal Pathway Signal Transduction Testing Therapeutic Thrombin Thrombin Receptor Time Transgenic Mice Work activated Protein C acute chest syndrome aging population beta Globin combat extracellular genetic manipulation insight mortality mouse model multimodality mutant premature receptor sickling thromboinflammation vascular inflammation vaso-occlusive crisis

项目摘要

PROJECT SUMMARY Title: Biased PAR1 Agonism in Sickle Cell Disease Sickle cell disease (SCD) is caused by a single nucleotide mutation in the β-globin gene, resulting in altered red cell physiology that drives chronic hemolytic anemia and painful vaso-occlusive crisis (VOC) triggered by microvascular occlusion/stasis. VOC is the leading cause of hospitalizations of sickle cell patients. Activation of the main thrombin receptor, protease activated receptor 1 (PAR1), enhances the interactions between endothelial cells and sickle RBCs. In my recently published study, I demonstrated that PAR1 deficiency on nonhematopoietic cells or inhibition of PAR1 with vorapaxar attenuates microvascular stasis in a mouse model of SCD. In addition to thrombin, PAR1 is also activated by activated protein C (APC). The APC-mediated activation of PAR1 is referred to as “biased agonism” because it activates a different signaling pathway than thrombin and ultimately induces cytoprotective and anti-inflammatory effects. My central hypothesis is that canonical thrombin/PAR1 signaling contributes to microvascular stasis whereas non-canonical APC/PAR1 signaling reduces microvascular stasis and thromboinflammation. I hypothesize that inducing beneficial PAR1 biased signaling will be advantageous compared to complete PAR1 inhibition, which blocks the deleterious thrombin- dependent signaling as well as beneficial APC signaling. In the first aim I will compare the roles of thrombin/PAR1 and APC/PAR1 signaling on coagulation, inflammation, and microvascular stasis in sickle cell mice using mice with PAR1 point mutations that select for activation by either thrombin or APC. In the second aim, I will compare the therapeutic potential of a signaling-selective form of APC, 3K3A-APC, to two inhibitors of PAR1, parmodulin 2 and vorapaxar, on inflammation, microvascular stasis, and acute chest syndrome. Finally, in the third aim, I will investigate the effects of biased PAR1 agonism on mortality and end-organ damage in sickle mice. These studies will investigate the role of biased PAR1 signaling in the pathology of SCD.

项目摘要标题：镰状细胞病中的偏性PAR 1激动作用镰状细胞病（SCD）是由β-珠蛋白基因中的单核苷酸突变引起的，红细胞生理学改变，导致慢性溶血性贫血和疼痛性血管闭塞危象（VOC）由微血管闭塞/停滞引发。VOC是镰状细胞贫血住院的主要原因患者主要凝血酶受体蛋白酶激活受体1（PAR 1）的激活增强了凝血酶的活性。内皮细胞和镰状红细胞之间的相互作用。在我最近发表的研究中，我证明了非造血细胞上的PAR 1缺陷或用vorapaxar抑制PAR 1会减弱 SCD小鼠模型中的微血管停滞。除了凝血酶，PAR 1也被激活，活化蛋白C（APC）。APC介导的PAR 1激活被称为“偏向激动” 因为它激活的信号通路与凝血酶不同，和抗炎作用。我的中心假设是，经典的凝血酶/PAR 1信号传导导致微血管停滞，而非经典APC/PAR 1信号转导减少微血管淤滞和血栓炎症。我假设，诱导有益的PAR 1偏向信号将是与阻断有害凝血酶的完全PAR 1抑制相比，依赖性信号传导以及有益的APC信号传导。在第一个目标中，我将比较凝血酶/PAR 1和APC/PAR 1信号对凝血、炎症和微血管淤滞的影响镰状细胞小鼠，使用具有PAR 1点突变的小鼠，选择通过凝血酶或装甲运兵车在第二个目标中，我将比较APC的信号选择性形式的治疗潜力， 3 K3 A-APC与PAR 1的两种抑制剂parmodulin 2和vorapaxar对炎症、微血管瘀滞和急性胸部综合征。最后，在第三个目标中，我将研究有偏PAR 1的影响对镰状小鼠死亡率和终末器官损伤的激动作用。这些研究将调查的作用，在SCD的病理学中偏置PAR 1信号传导。