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

基本信息

批准号：
10242175
负责人：
SATORU EGUCHI
金额：
$ 43.51万
依托单位：
ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10242175
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 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

项目摘要

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.

项目概要该多 PI R01 提案建立在两个相关但不同的 PI 之间持续合作的基础上专业知识集。桥本拥有颅内动脉瘤转化研究方面的专业知识。江口是一个心血管疾病肾素-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发展机制。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机制是不清楚。可能存在介导动脉瘤破裂和高血压的常见信号通路血管重塑导致终末器官损伤。抗高血压治疗的预防效果动脉瘤破裂的风险尚未在人类中确定。因为单纯降低血压并不能完全逆转与高血压相关的终末器官损伤，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。血管壁中血管紧张素 II (AngII) 的局部产生正在成为血管紧张素II (AngII) 的关键机制。促进血管炎症、过度重塑和与相关的终末器官损伤高血压。临床研究表明局部 RAS 与颅内血管破裂之间存在潜在联系动脉瘤。 Hashimoto 发现小鼠模型的动脉瘤壁中 AngII 水平升高颅内动脉瘤。此外，局部AngII的药理学阻断可防止动脉瘤破裂。 Eguchi 证明 AngII 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 ER 应激导致病理性血管重塑。基于这些发现，我们提出局部 AngII 激活 ADAM17 会导致 EGFR 激活和 TNFa 产生，两者都会增加 ER 应激并促进动脉瘤破裂。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，涉及 ADAM17 和 ER 应激。这种信号环路会导致持续的炎症和壁损伤，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 以及随后诱导 ER 应激。目标 2 是测试 EGFR 激活是否通过诱导 ER 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、ER应激组成的信号环路。拟议的研究将确定 ADAM17 之后 EGFR 反式激活和 TNFa 的产生激活是促进内质网应激和随后动脉瘤破裂的关键途径。内的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。