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Characterization of Atypical p38 signaling in Acute Lung Injury

急性肺损伤中非典型 p38 信号传导的特征

基本信息

批准号：
10518051
负责人：
Neil J Grimsey
金额：
$ 7.21万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-10 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10518051
关键词：
2019-nCoV Acute Lung Injury Acute Respiratory Distress Syndrome Adaptor Signaling Protein Address Adherens Junction Alveolar Amyloidosis Anti-Inflammatory Agents Attenuated Binding Blood Vessels Bronchoalveolar Lavage Bypass Cells Clinic Coagulation Process Complement Conceptions Connexin 43 Data Dermal Disease Disease Progression Edema Electrical Resistance Endothelial Cells Endothelium Extravasation Foundations Functional disorder Future G-Protein-Coupled Receptors Goals Histologic Human Immune In Vitro Infiltration Inflammation Inflammatory Inflammatory Response Intervention Investments Knock-in Mouse Knowledge Link Lipopolysaccharides Lung Lung diseases MAP3K7IP1 gene Macrophage Activation Mediator of activation protein Modeling Molecular Mus Neutrophil Activation Neutrophil Infiltration Pathologic Pathway interactions Patients Peptides Pericytes Phase Phenotype Physiological Pilot Projects Play Production Protein Isoforms Pulmonary Edema Pulmonary Inflammation Regulation Role Signal Pathway Signal Transduction Syndrome Therapeutic Tight Junctions Tissues Vascular Diseases Vascular Endothelial Cell Virus Diseases Wild Type Mouse Work alveolar epithelium cadherin 5 cytokine experimental study heart damage improved outcome in vivo in vivo Model inhibitor innovation lung injury lung microvascular endothelial cells macrophage migration neutrophil novel therapeutics p38 Mitogen Activated Protein Kinase pulmonary function recruit response therapeutic candidate therapeutic development therapeutic target therapeutically effective vascular inflammation

项目摘要

Mitogen-activated protein kinase (MAPK) p38 is a critical mediator of vascular disruption/edema and inflammatory signaling associated with acute lung injury (ALI), acute respiratory distress syndrome (ARDS). However, p38 directed therapeutics have failed in the clinic due to the physiologically ubiquitous role of p38 activity in all tissues. Thus, there is an essential need to explore alternative mechanisms that selectively regulate pathological p38 signaling pathways. An understudied atypical p38 activation pathway has recently been discovered that selectively regulates pathological signaling induced via a direct p38 interaction with the adaptor protein TAB1, independent from classical p38 activation by MKK3/6. The role of this underexplored pathway in pulmonary function has not been investigated, representing a major gap in our molecular knowledge of ALI/ARDS. P38 signaling is known to regulate inflammatory cytokine expression, vascular dysfunction, macrophage and neutrophil activation and recruitment, enhancing the progression of pulmonary damage. Atypical p38 signaling in the vasculature rapidly induces production of inflammatory cytokine expression and blood vessel leakage, and macrophage recruitment. The goal of these studies is to understand the physiological impact that atypical MAPK p38 signaling has in pulmonary vasculature during the initial stages of LPS induced acute lung injury, and its contribution to pulmonary damage. Our central hypothesis disruption, alveolar damage, is that atypical p38 activation plays a key role in propagating vascular and pulmonary inflammatory responses in acute lung injury. From this hypothesis we propose two specific aims: 1) Characterize the contribution of atypical p38 signaling to pulmonary edema/vascular dysregulation, 2) Characterize atypical p38 pro-inflammatory responses in ALI. We will also use an acute lung injury (ALI) model using lipopolysaccharide (LPS) in a systemic TAB1-KI mouse verses wild-type mouse and a cell-penetrating inhibitor peptide which can block atypical p38 signaling. We predict that blockade of atypical p38 signaling will significantly reduce pulmonary edema in vivo and establish a critical role in endothelial barrier dysregulation in vitro and in vivo. Furthermore, we predict that these studies will demonstrate a clear role for atypical p38 signaling in cytokine expression, leading to activation and recruitment of neutrophils and macrophages. Critically, these studies will be the first to define the role of atypical p38 signaling in acute lung injury and provide essential foundational evidence for further more detailed studies into pulmonary atypical p38 signaling. Furthermore, these studies will demonstrate the future therapeutic potential for selectively inhibiting atypical p38 signaling in vascular and pulmonary inflammatory diseases.

丝裂原活化蛋白激酶(MAPK)p38是血管破裂/水肿的关键介质。与炎症信号相关的急性肺损伤(ALI)、急性呼吸窘迫综合征(ARDS)。然而，由于p38在生理上无处不在的作用，p38的定向治疗在临床上失败了。所有组织中的活性。因此，有必要探索选择性监管的替代机制。病理性p38信号通路。最近，一个未被充分研究的非典型p38激活途径发现选择性地调节通过与适配器直接的p38相互作用而诱导的病理信号 Tab1蛋白，独立于经典的p38由MKK3/6激活。这一未被探索的途径的作用在肺功能方面还没有被研究，这代表了我们在分子知识上的一个重大差距 ALI/ARDS的。已知p38信号调节炎症细胞因子的表达，血管功能障碍，巨噬细胞和中性粒细胞的激活和募集，促进了肺损伤的进展。非典型p38信号转导在血管中迅速诱导炎性细胞因子的表达和血管渗漏，以及巨噬细胞募集。这些研究的目的是了解非典型MAPK对生理的影响 P38信号通路在内毒素致急性肺损伤早期肺血管中的表达及其意义对肺损伤的贡献。我们的中心假设肺破裂，肺泡损伤，非典型的p38激活在血管的传播中起着关键作用急性肺损伤时的肺炎性反应。由此假设我们提出了两个具体的目标：1)表征非典型p38信号对肺组织的作用 2)ALI中非典型的p38促炎反应。我们还将使用脂多糖诱导的TAB1-KI小鼠急性肺损伤模型与野生型比较小鼠和一种可以阻断非典型p38信号的细胞穿透抑制物肽。我们预测封锁非典型p38信号通路将显著减轻体内的肺水肿，并在体内和体外内皮屏障调节失调。此外，我们预测这些研究将证明非典型p38信号在细胞因子表达中的明显作用，导致中性粒细胞的激活和募集和巨噬细胞。关键的是，这些研究将首次确定非典型p38信号在急性胰腺炎中的作用。为更详细地研究肺非典型肺炎提供了必要的基础证据 P38信号。此外，这些研究将展示未来选择性治疗的潜力。抑制血管和肺部炎症性疾病中的非典型p38信号。