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: 10686891
• 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/10686891
• 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; Link; Mediating; Metalloproteases; Molecular; Mus; Organ; Paper; Pathologic; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; 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; Stress; Techniques; Testing; Tissues; Transactivation; Translational Research; Vascular Smooth Muscle; Vascular remodeling; blood pressure reduction; cell type; cytokine; endoplasmic reticulum stress; experimental study; hypertensive; in vivo; inhibitor; mouse model; novel; pharmacologic; 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 该多PI R01提案是建立在两个PI之间的持续合作的基础上的， 专业知识集。 Hashimoto在颅内动脉瘤的翻译研究方面具有专业知识。 Eguchi是一个 心血管疾病中肾素 - 血管紧张素系统（RAS）的专家。结合两组专业知识，我们 将研究开发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 亚蛛网膜下腔出血）。但是，高血压促进动脉瘤破裂的机制是 不清楚。可能有常见的信号通路可以介导动脉瘤破裂和高血压 - 导致最终器官损伤的血管重塑。抗高血压治疗的预防功效 人类尚未建立动脉瘤破裂。因为简单降低血压不会 与高血压相关的完全反向末端器官损伤，预防动脉瘤破裂 可能需要针对由高血压触发的下游事件的药理疗法。 血管壁中血管紧张素II（Angii）的局部生产正在成为作为关键机制 促进血管炎症，过度重塑和与终极器官损害相关的损害 高血压。临床研究表明，局部RA与颅内破裂之间的潜在联系 动脉瘤。 Hashimoto显示了小鼠模型的动脉瘤壁中的血管肌水平升高 颅内动脉瘤。此外，局部Angii的药理阻滞阻止了动脉瘤破裂。 Eguchi表明，Angii的ADAM17激活导致表皮生长因子的激活 血管平滑肌细胞中的受体（EGFR）。我们的协作论文表明，激活 ADAM17和EGFR通过诱导ER应激导致病理血管重塑。 基于这些发现，我们建议局部Angii的ADAM17激活导致EGFR 激活和TNFA产生，两者都会增加ER应力并促进动脉瘤破裂。我们也是 提出有一个信号循环，该循环由进料和馈回信号通路组成 涉及ADAM17和ER应力。这种信号循环会导致持续的炎症和墙壁伤害 导致动脉瘤破裂。 AIM 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以及随后的ER应力诱导。目标2是测试 EGFR激活是否通过诱导ER应力导致动脉瘤破裂。目标3是测试 是否存在由ADAM17激活，EGFR / TNFA的激活和ER应力的信号循环。 拟议的研究将在ADAM17之后建立EGFR反式激活和TNFA产生 激活作为促进ER应力和随后的动脉瘤破裂的关键途径。内部的分子步骤 途径代表了预防动脉瘤破裂的潜在治疗靶标。