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.

严重脓毒症是一种常见的、昂贵的、往往是致命的疾病，是导致 在美国的重症监护室。通常，50%的脓毒症病例始于肺部感染，绝大多数 4例发展为单微生物败血症。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定植于血管内导管或外科手术的能力 植入材料，以及耐抗生素金黄色葡萄球菌的传播，如耐甲氧西林金黄色葡萄球菌 (MRSA)。脓毒症通常伴有多器官功能障碍、细胞因子风暴、播散性 凝血综合征常常引起间接肺损伤，最终导致急性呼吸窘迫综合征 (ARDS)。ARDS也是正在进行的新冠肺炎导致呼吸衰竭和死亡的主要手段 大流行。没有有效的药物干预措施来治疗ARDS；相反，目前的治疗主要是 仅限于通过机械通风进行呼吸支持；然而，通气量不佳可能 加重甚至引起新生的肺损伤。ARDS的特点是细胞因子和趋化因子水平升高， 炎性细胞渗入、纤维化和血管完整性丧失。 这个项目将检验一个新的假设，即机械敏感的质子传感受体GPR68是一个关键 可能控制原发性肺炎症程度的ARDS病理生理学介质 感染损害和减轻ARDS的严重程度，与不理想的机械通气相关。我们将对此进行测试 假设使用我们的新型一流小分子GPR68抑制剂，由我们的小组通过四个 具体目的：1)研究促炎因子激活GPR68的分子机制。 体外和体外炎性肺损伤模型；2)研究GPR68在调控肺损伤中的功能作用。 肺内皮细胞对ARDS相关损伤的反应；3)检测GPR68的机械敏感性调节 活性；4)评价药物GPR68抑制物减轻肺损伤的治疗潜力 细菌性ALI一次击打和两次击打小鼠模型的功能障碍。 通过更好地了解GPR68如何导致肺屏障功能障碍，并确定其 抑制可以改善ARDS的表型，我们将能够开发和测试新的治疗药物 ARDS合并败血症、细菌、病毒感染、化学损伤、输血相关肺的治疗 受伤和其他。