EGF-ADAM17 axis in the pathophysiology of intracranial aneurysm

项目摘要 此多PI R01提案建立在两个PI之间的持续协作基础上，这些PI具有相关但不同的 一整套专业知识。桥本在颅内动脉瘤的翻译研究方面拥有专业知识。江口是一个 心血管疾病中肾素-血管紧张素系统(RAS)方面的专家。结合两套专业知识，我们 将研究颅内动脉瘤破裂的发生机制。 高血压被认为是颅内动脉瘤(即动脉瘤)破裂的危险因素。 蛛网膜下腔出血)。然而，高血压促进动脉瘤破裂的一个机制是 不清楚。可能有共同的信号通路同时介导动脉瘤破裂和高血压- 导致终末器官损伤的血管重塑。降压治疗预防高血压的疗效观察 动脉瘤破裂的可能性在人类中尚未得到证实。因为简单的降压并不能 完全逆转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。 血管壁上局部产生的血管紧张素II(AngII)正在成为 促进与以下相关的血管炎症、过度重构和终末器官损伤 高血压。临床研究提示局部RAS与颅内破裂之间存在潜在联系 动脉瘤。桥本已经展示了在小鼠脑动脉瘤模型中血管紧张素Ⅱ水平的增加。 颅内动脉瘤。此外，局部血管紧张素Ⅱ的药理阻断防止了动脉瘤破裂。 江口已证明，血管紧张素转换酶激活ADAM17会导致表皮生长因子的激活 血管平滑肌细胞中的受体(EGFR)。我们的合作论文表明，激活 ADAM17和EGFR通过诱导内质网应激导致病理性血管重构。 基于这些发现，我们认为ADAM17被局部血管紧张素Ⅱ激活导致了EGFR 激活和TNFa的产生，两者都增加了内质网应激，促进了动脉瘤破裂。我们也 提出存在一个由前馈和反馈信号通路组成的信号环路， 参与ADAM17和内质网应激。这种信号环路会导致持续的炎症和室壁损伤 导致动脉瘤破裂。目的1是测试ADAM17的激活是否促进动脉瘤破裂 通过激活EGFR，产生TNFa，继而诱导内质网应激。目标2是测试 EGFR活化是否通过内质网应激导致动脉瘤破裂。目标3是测试 是否存在由ADAM17激活、EGFR/TNFa激活和内质网应激组成的信号循环。 拟议的研究将在ADAM17之后建立EGFR反式激活和TNFa产生 激活是促进内质网应激和随后的动脉瘤破裂的关键途径。分子步长内 这些通路是预防动脉瘤破裂的潜在治疗靶点。

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.