GPR68 as a novel modulator of septic lung injury

GPR68 作为脓毒性肺损伤的新型调节剂

基本信息

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
项目类别：
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

项目摘要

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.

严重败血症是一种常见、昂贵且常常致命的疾病，是导致死亡的主要原因美国的ICU。通常，50% 的脓毒症病例始于肺部感染，并且绝大多数病例发展为单一微生物败血症。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能够定植于血管内导管或通过手术植入材料，以及耐抗生素金黄色葡萄球菌的传播，例如耐甲氧西林金黄色葡萄球菌（耐甲氧西林金黄色葡萄球菌）。脓毒症通常伴有多器官功能障碍、细胞因子风暴、播散性凝血综合征经常引起间接肺损伤，最终导致急性呼吸窘迫综合征（ARDS）。 ARDS 也是持续的 COVID-19 导致呼吸衰竭和死亡的主要途径大流行。 ARDS 尚无有效的药物干预措施；相反，目前的治疗主要是仅限于通过机械通气进行呼吸支持；然而，次优通气量可能会加重甚至导致新发肺损伤。 ARDS 的特点是细胞因子和趋化因子水平升高，炎症细胞浸润、纤维化和血管完整性丧失。该项目将测试一个新的假设，即机械敏感质子传感受体 GPR68 是一个关键 ARDS 病理生理学的介质，可能控制原发性肺部炎症的程度感染损伤并减轻与次优机械通气相关的 ARDS 严重程度。我们将测试这个使用我们团队通过四个阶段开发的新型一流小分子 GPR68 抑制剂进行假设具体目标： 1) 研究促炎因子激活 GPR68 的分子机制炎性肺损伤的体外和离体模型； 2) 研究GPR68在调节中的功能作用肺内皮对 ARDS 相关损伤的反应； 3) 检查GPR68的机械敏感调节活动; 4) 评估药物 GPR68 抑制缓解肺损伤的治疗潜力细菌性 ALI 的一击和二击小鼠模型中的功能障碍。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药物治疗与败血症、细菌、病毒感染、化学损伤、输血相关肺相关的ARDS 伤害及其他。