Biased PAR1 Agonism in Sickle Cell Disease

镰状细胞病中 PAR1 激动的偏向性

• 批准号: 10327643
• 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
• 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/10327643
• 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; Persons; 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

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.

项目概要 标题：镰状细胞病中 PAR1 激动的偏向 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，导致 红细胞生理学改变导致慢性溶血性贫血和痛苦的血管闭塞危象 (VOC) 由微血管闭塞/瘀滞触发。 VOC是镰状细胞病住院的主要原因 患者。主要凝血酶受体蛋白酶激活受体 1 (PAR1) 的激活可增强 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 PAR1 缺陷或用 vorapaxar 抑制 PAR1 会减弱 SCD 小鼠模型中的微血管停滞。除凝血酶外，PAR1 也可被激活 活化蛋白C (APC)。 APC 介导的 PAR1 激活被称为“偏向激动” 因为它激活与凝血酶不同的信号通路并最终诱导细胞保护 和抗炎作用。我的中心假设是规范的凝血酶/PAR1 信号传导 导致微血管停滞，而非规范的 APC/PAR1 信号传导则减少微血管 瘀滞和血栓炎症。我假设诱导有益的 PAR1 偏向信号传导将是 与完全抑制 PAR1 相比是有利的，后者会阻止有害的凝血酶 依赖性信号传导以及有益的 APC 信号传导。在第一个目标中，我将比较以下角色 凝血酶/PAR1和APC/PAR1信号传导对凝血、炎症和微血管瘀滞的影响 镰状细胞小鼠使用带有 PAR1 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，我将比较信号选择性形式的 APC 的治疗潜力， 3K3A-APC，针对 PAR1 的两种抑制剂，parmodulin 2 和 vorapaxar，对炎症、微血管 气滞、急胸证。最后，在第三个目标中，我将研究偏向 PAR1 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 SCD 病理学中偏向的 PAR1 信号传导。