GPR68 as a novel modulator of septic lung injury

GPR68 作为脓毒性肺损伤的新型调节剂

• 批准号: 10743219
• 负责人: Anna Birukova
• 金额: $ 62.16万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10743219
• 关键词: Acids; Acute Lung Injury; Acute Respiratory Distress Syndrome; Adhesions; Animal Model; Antibiotic Resistance; Bacterial Model; Blood Vessels; COVID-19 pandemic; Cardiology; Catheters; Cause of Death; Caveolins; Cell model; Cell physiology; Cells; Cessation of life; Chemical Injury; Coagulation Process; Collaborations; Communities; Data; Development; Discipline; Disease; Endothelial Cells; Endothelium; Extravasation; Fibrosis; Frequencies; Functional disorder; G-Protein-Coupled Receptors; GPR68 gene; Human; In Vitro; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Intervention; Investigation; Knowledge; Lung; Lung infections; Mechanical ventilation; Mechanics; Mediating; Mediator; Modality; Modeling; Molecular; Morbidity - disease rate; Operative Surgical Procedures; Organ; Pathologic; Patients; Periodicity; Phenotype; Primary Infection; Production; Protons; Pulmonary Inflammation; Regulation; Reporting; Resolution; Respiratory Failure; Role; Scientist; Sepsis; Severities; Signal Transduction; Staphylococcus aureus; Stimulus; Stretching; Syndrome; TLR2 gene; Testing; Therapeutic; Therapeutic Agents; Tidal Volume; Tissues; Transfusion; United States; Vascular Endothelium; Viral; Virus Diseases; analog; attenuation; chemokine; cytokine; cytokine release syndrome; drug discovery; effective therapy; fighting; implant material; in vivo; in vivo Model; inflammatory milieu; inhibitor; lung injury; mechanical stimulus; methicillin resistant Staphylococcus aureus; mortality; mouse model; neutrophil; novel; novel therapeutics; pathogenic bacteria; pharmacologic; receptor; respiratory; response; sensor; septic; small molecule; small molecule inhibitor; ventilation; virtual

Severe sepsis is a common, expensive, and frequently fatal condition which is the leading cause of death in the ICU in the United States. Typically, 50% of all sepsis cases start as a pulmonary infection and vast majority of cases develop as mono-microbial sepsis. Alarming reports indicate that the frequency of gram-positive sepsis has been increasing, likely due to the ability of S. aureus to colonize intravascular catheters or surgically implanted materials, as well as the spread of antibiotic-resistant S. aureus, such as methicillin-resistant S. aureus (MRSA). Sepsis is typically accompanied by multiple organ dysfunction, cytokine storm, disseminated coagulation syndrome that often provoke indirect lung injury culminating in Acute Respiratory Distress Syndrome (ARDS). ARDS is also the primary means of respiratory failure and deaths from the ongoing COVID-19 pandemic. There are no effective pharmacological interventions for ARDS; rather, current treatment is primarily limited to respiratory support through mechanical ventilation; however, suboptimal ventilation volumes can worsen or even cause de novo lung injury. The hallmarks of ARDS are increased cytokine and chemokine levels, inflammatory cell infiltrates, fibrosis, and loss of vascular integrity. This project will test a novel hypothesis that mechano-sensitive proton sensing receptor GPR68 is a key mediator of ARDS pathophysiology that might control the magnitude of lung inflammation initiated by primary infection insult and mitigate ARDS severity associated with suboptimal mechanical ventilation. We will test this hypothesis using our novel first-in-class small molecule GPR68 inhibitor developed by our group through four specific aims: 1) To examine molecular mechanisms of GPR68 activation by pro-inflammatory factors in the in vitro and ex vivo models of inflammatory lung injury; 2) To study the functional role of GPR68 in modulation of pulmonary endothelial response to ARDS-related insults; 3) To examine mechano-sensitive regulation of GPR68 activity; 4) To evaluate a therapeutic potential of pharmacological GPR68 inhibition for mitigation of lung dysfunction in one-hit and two-hit mouse models of bacterial ALI. By better understanding how GPR68 contributes to lung barrier dysfunction and determining whether its inhibition can ameliorate the ARDS phenotype, we will be able to develop and test novel therapeutic agents for treatment of ARDS associated with sepsis, bacterial, viral infection, chemical injury, transfusion related lung injury and other.

严重的败血症是一种常见，昂贵且经常致命的状况，这是死亡的主要原因 美国的ICU。通常，所有败血症病例中有50％以肺部感染和绝大多数开始 病例随着单微生物败血症而发展。令人震惊的报告表明革兰氏阳性败血症的频率 一直在增加，可能是由于金黄色葡萄球菌在血管内导管或外科手术的能力上 植入的材料以及抗生素耐药性金黄色葡萄球菌的扩散，例如耐甲氧西林的金黄色葡萄球菌 （MRSA）。败血症通常伴有多个器官功能障碍，细胞因子风暴，散布 凝血综合征经常引起间接肺部损伤高潮 （ARDS）。 ARDS也是呼吸衰竭和正在进行的Covid-19的主要手段 大流行。 ARDS没有有效的药理干预措施；相反，当前的治疗主要是 通过机械通气限制呼吸支持；但是，次优的通气量可以 恶化甚至造成从头肺损伤。 ARD的标志是细胞因子和趋化因子水平增加， 炎性细胞浸润，纤维化和血管完整性的丧失。 该项目将检验一个新的假设，即机械敏感的质子传感受体GPR68是关键 ARDS病理生理介质可能控制原发性肺部炎症的大小 感染侮辱和减轻与次优的机械通气相关的ARDS严重程度。我们将测试这个 假设使用我们小组通过四个开发的新型一流的小分子GPR68抑制剂 具体目的：1）检验促炎因子在IN中激活GPR68的分子机制 体外和离体炎性肺损伤模型； 2）研究GPR68在调制中的功能作用 肺内皮反应对ARDS相关的损伤； 3）检查GPR68机械敏感的调节 活动; 4）评估药理学GPR68抑制肺的治疗潜力 细菌ALI的一击和两击小鼠模型中的功能障碍。 通过更好地了解GPR68如何促进肺屏障功能障碍并确定其是否是否 抑制可以改善ARDS表型，我们将能够开发和测试新的治疗剂 与败血症，细菌，病毒感染，化学损伤，相关肺有关的ARDS治疗 受伤和其他。