EGF-ADAM17 axis in the pathophysiology of intracranial aneurysm

EGF-ADAM17轴在颅内动脉瘤病理生理学中的作用

• 批准号: 10024093
• 负责人: SATORU EGUCHI
• 金额: $ 43.91万
• 依托单位: ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10024093
• 关键词: Affect; Aneurysm; Aneurysmal Subarachnoid Hemorrhages; Angiotensin II; Antihypertensive Agents; Archives; Blood Vessels; Brain; Cardiovascular Diseases; Cell Culture System; Cell Culture Techniques; Clinical Research; Collaborations; Development; EGF gene; Endoplasmic Reticulum; Epidermal Growth Factor Receptor; Estrogen receptor positive; Event; Feedback; Functional disorder; Growth Factor Receptors; Hormones; Human; Hypertension; In Vitro; Inflammation; Intracranial Aneurysm; Knockout Mice; Lead; Link; Mediating; Metalloproteases; Molecular; Mus; Organ; Paper; Pathologic; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacology; Prevention; Production; Receptor Activation; Receptor Inhibition; Renin-Angiotensin System; Risk Factors; Role; Rupture; Ruptured Aneurysm; Signal Pathway; Signal Transduction; Small Interfering RNA; Smooth Muscle Myocytes; Specimen; Techniques; Testing; Tissues; Transactivation; Translational Research; Vascular Smooth Muscle; Vascular remodeling; base; blood pressure reduction; cell type; cytokine; endoplasmic reticulum stress; experimental study; hypertension prevention; in vivo; inhibitor/antagonist; mouse model; novel; prevent; targeted treatment; therapeutic target; vascular inflammation

Project Summary This multi-PI R01 proposal is built upon an ongoing collaboration between two PIs with related but distinct sets of expertise. Hashimoto has expertise in the translational research of intracranial aneurysm. Eguchi is an expert in the renin-angiotensin system (RAS) in cardiovascular diseases. Combining two sets of expertise, we will study the mechanisms for the development of intracranial aneurysm rupture. Hypertension is considered a risk factor for the rupture of intracranial aneurysm (i.e., aneurysmal subarachnoid hemorrhage). However, a mechanism by which hypertension promotes aneurysmal rupture is unclear. There may be common signaling pathways that mediate both aneurysmal rupture and hypertensive- vascular remodeling that leads to end-organ damage. Efficacy of anti-hypertensive treatment for the prevention of aneurysmal rupture has not been established in humans. As simple reduction of blood pressure does not completely reverse end-organ damage associated with hypertension, the prevention of aneurysmal rupture may require pharmacological therapies that target down-stream events triggered by hypertension. Local production of angiotensin II (AngII) in the vascular wall is emerging as a key mechanism for the promotion of vascular inflammation, excessive remodeling, and end-organ damages that are associated with hypertension. Clinical studies suggest a potential link between the local RAS and the rupture of intracranial aneurysms. Hashimoto has shown the increased AngII levels in the aneurysmal walls of a mouse model of intracranial aneurysm. Moreover, the pharmacological blockade of local AngII prevented aneurysmal rupture. Eguchi has shown that the activation of ADAM17 by AngII leads to the activation of epidermal growth factor receptor (EGFR) in vascular smooth muscle cells. Our collaborative papers have shown that the activation of ADAM17 and EGFR leads to pathological vascular remodeling through the induction of ER stress. Based on these findings, we propose that the activation of ADAM17 by the local AngII leads to EGFR activation and TNFa production, both of which increase ER stress and promote aneurysm rupture. We also propose that there is a signaling loop composed of the feed-forward and feed-back signaling pathways that involve ADAM17 and ER stress. This signaling loop causes the sustained inflammation and wall damage that leads to aneurysmal rupture. Aim 1 is to test whether the activation of ADAM17 promotes aneurysmal rupture through the activation of EGFR, production of TNFa, and subsequent induction of ER stress. Aim 2 is to test whether the EGFR activation leads to aneurysmal rupture through induction of ER stress. Aim 3 is to test whether there is a signaling loop composed of ADAM17 activation, activation of EGFR / TNFa, and ER stress. The proposed studies will establish EGFR trans-activation and TNFa production following ADAM17 activation as key pathways that promote ER stress and subsequent aneurysm rupture. Molecular steps within the pathways represent potential therapeutic targets for the prevention of aneurysm rupture.

项目摘要 此多PI R 01提案建立在两个PI之间的持续合作基础上，这些PI相关但不同 一套专业知识。桥本在颅内动脉瘤的转化研究方面具有专长。江口是一个 心血管疾病中的肾素-血管紧张素系统（RAS）专家。结合两套专业知识，我们 将研究颅内动脉瘤破裂的机制。 高血压被认为是颅内动脉瘤破裂的危险因素（即，动脉瘤 蛛网膜下腔出血）。然而，高血压促进膀胱破裂的机制是 不清楚可能有共同的信号通路介导动脉瘤破裂和高血压- 导致终末器官损伤的血管重塑抗高血压治疗对预防高血压的疗效 在人类中还没有发现子宫肌瘤破裂。因为单纯的降低血压并不能 完全逆转与高血压相关的终末器官损害，预防动脉瘤破裂 可能需要针对高血压引发的下游事件的药物治疗。 血管壁局部产生血管紧张素II（AngII）是血管紧张素II缺乏的关键机制。 促进血管炎症、过度重塑和终末器官损伤， 高血压临床研究表明局部RAS与颅内动脉瘤破裂之间存在潜在联系。 动脉瘤Hashimoto已经证明，在一个小鼠模型的血管紧张素II水平增加， 颅内动脉瘤此外，局部血管紧张素II的药理学阻断可防止动脉瘤破裂。 江口已经表明，血管生成素II激活ADAM 17导致表皮生长因子激活 血管平滑肌细胞中EGFR的表达。我们的合作论文表明， ADAM 17和EGFR通过诱导ER应激导致病理性血管重构。 基于这些发现，我们认为局部AngII激活ADAM 17导致EGFR 激活和TNF α产生，这两者都增加ER应激并促进动脉瘤破裂。我们也 提出存在由前馈和反馈信号通路组成的信号回路， 涉及ADAM 17和ER应激。这种信号循环导致持续的炎症和壁损伤， 导致子宫内膜破裂目的1是检测ADAM 17的激活是否促进了脑血管破裂 通过EGFR的活化、TNF α的产生和随后的ER应激的诱导。目标2：测试 EGFR的激活是否通过诱导ER应激而导致囊性破裂。目标3：测试 是否存在由ADAM 17激活、EGFR / TNFa激活和ER应激组成的信号环。 拟议的研究将确定ADAM 17后EGFR的反式激活和TNF α的产生。 激活作为促进ER应激和随后的动脉瘤破裂的关键途径。分子步骤 这些通路代表了预防动脉瘤破裂的潜在治疗靶点。