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：
10544152
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/10544152
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 Cytoprotection Data Disease Disease Management Endothelial Cells Endothelium Erythrocytes Etiology Functional disorder G-Protein-Coupled Receptors Generations Genes Genetic Goals Hemolytic Anemia Hospitalization Human Infection Inflammation Inflammatory Response Lead Long-Term Effects Longevity Mediating Mediator Methods Mus Mutation Newborn Infant Nucleotides Organ Oxidative Stress PAR-1 Receptor Pain Pathology Patients Persons Pharmaceutical Preparations Point Mutation Protease Inhibitor Publishing Reperfusion Injury Role Sickle Cell Sickle Cell Anemia Signal Induction 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 improved insight mortality mouse model multimodality mutant pharmacologic 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：镰状细胞疾病中的PAR1激动剂有偏见镰状细胞疾病（SCD）是由β-珠蛋白基因中的单个核苷酸突变引起的，导致改变的红细胞生理学，驱动慢性溶血性贫血和疼痛的血管成熟危机（VOC）由微血管闭塞/暂停触发。 VOC是镰状细胞住院的主要原因患者。主凝血酶受体的激活，蛋白酶激活受体1（PAR1），增强了内皮细胞和镰状RBC之间的相互作用。在我最近发表的研究中，我证明了 pAR1缺乏非杂造细胞或抑制vorapaxar衰减的PAR1 SCD小鼠模型中的微血管滞留。除凝血酶外，PAR1还被激活活化的蛋白C（APC）。 APC介导的PAR1激活称为“偏见激动剂” 因为它激活了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凝血酶/PAR1信号传导有助于微血管滞留停滞和血栓炎。我假设引起的有益PAR1有偏见的信号传导将是与完整的PAR1抑制相比依赖信号传导以及有益的APC信号。在第一个目标中，我将比较凝血素/PAR1和APC/PAR1信号传导在凝结，注射和微血管暂停中使用PAR1点突变的小鼠镰状细胞小鼠选择凝血酶或凝血酶的激活 APC。在第二个目标中，我将比较APC的信号选择形式的治疗潜力 3K3A-APC，到两个PAR1，parmodulin 2和Vorapaxar的两个抑制剂，在注射时，微血管停滞和急性胸部综合征。最后，在第三个目标中，我将研究有偏见的PAR1的影响镰状小鼠死亡率和最终器官损害的激动作用。这些研究将研究 SCD病理中的偏置PAR1信号传导。