Targeting ADAM17 maturation in resistant hypertension.

靶向顽固性高血压中 ADAM17 的成熟。

• 批准号: 10432585
• 负责人: ERIC D LAZARTIGUES
• 金额: $ 57.83万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10432585
• 关键词: ACE2; Affect; Age; Aldosterone; Angiotensin II; Blood Pressure; Bone Marrow; Brain; CX3CL1 gene; Cardiovascular Diseases; Cardiovascular system; Cell membrane; Cells; DOCA; Data; Development; Disintegrins; Drug Targeting; Experimental Models; Gene Deletion; Genetic Models; Genetically Engineered Mouse; Heart; Human; Hypertension; Hypothalamic structure; In Vitro; Individual; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-6; Kidney; Knockout Mice; Lead; Maintenance; Mediating; Medical; Metalloproteases; Microglia; Molecular; Mus; Nerve; Neurons; Organ; Peptidyl-Dipeptidase A; Physiological; Prevalence; Process; Proteins; Public Health; Regulation; Renin-Angiotensin System; Reporting; Resistance development; Resistant Hypertension; Risk Factors; Role; Signal Transduction; Sodium Chloride; Stimulus; Synapses; TNF gene; Testing; Time; Tissues; Transgenic Organisms; United States; Up-Regulation; Vasopressins; Water; Work; aged; base; blood pressure reduction; clinically relevant; conditional knockout; cytokine; exosome; human stem cells; hypertension treatment; hypertensive; improved; in vivo; inhibitor; knock-down; mortality; neurogenic hypertension; neuroinflammation; novel; overexpression; paraventricular nucleus; prevent; receptor; rhomboid; salt sensitive hypertension; vasoconstriction

With prevalence as high as 55% for individuals aged 55 and older in United States, hypertension (HTN) is a major risk factor contributing to cardiovascular diseases (CVD) and global mortality, hence remaining an increasingly important medical and public health issue. The role of the brain renin-angiotensin system (RAS) in the maintenance of normal blood pressure (BP) and in the neuro-cardiovascular dysregulation leading to HTN has been firmly established. Angiotensin (Ang)-II, by means of its type 1 receptor (AT1R), promotes increased sympathetic nerve activity, salt and water reabsorption, vasoconstriction, aldosterone and vasopressin release and inflammation, all contributing to HTN. While numerous overexpression studies, from our group and others, have established the benefits of ACE2 (Angiotensin Converting Enzyme type 2) in preventing the progression and improving the treatment of HTN in experimental models, our group was the first to demonstrate that ADAM17 (A Disintegrin And Metalloprotease) mediates ACE2 shedding in neurogenic HTN, thus reducing ACE2 compensatory activity in mice and humans. ADAM17-mediated ACE2 shedding, a process by which the protein ectodomain is cleaved from the plasma membrane and secreted into the surrounding milieu, has since been confirmed in many tissues including heart and kidney. ADAM17 is thought to mediate neuroinflammation through soluble TNFα, IL-6 trans-signaling, CX3CL1 and other cytokines, yet this mechanism has not been studied in neurogenic HTN. DOCA-salt HTN is associated with increased levels of TNFα, IL-6 and reduced ACE2 activity in the brain, while deletion of ADAM17 from neurons reduces BP, restores ACE2 activity and decreases pro- inflammatory cytokines. Although ADAM17 is thought to be a major drug target for inflammation, the development of selective inhibitors has failed. Recent work, deemed revolutionary, shows that ADAM17 maturation is tightly regulated by rhomboid proteins in the brain (iRhom1 in neurons and iRhom2 in microglia), opening the door for novel targeting strategies. Accordingly, we hypothesize that targeting ADAM17 maturation will reverse sympatho-excitation and neuro-inflammation in neurogenic HTN. We will test this new targeting strategy in the following two specific aims. Using a combination of human stem cells-derived neurons and microglia, unique transgenic and conditional knockout mice, with selective deletion of ADAM17 in microglia (Cx3Cr1ERT2-ADAM17tom) and targeted knockdown of ADAM17 maturation in neurons (Rhom1) or microglia (iRhom2), the immediate objectives of this application are to: 1) Understand how ADAM17 upregulation takes place throughout pre-sympathetic networks; 2) Assess the feed-forward role of ADAM17 in neuro-inflammation and microglia activation; and 3) Test new clinically-relevant targeting strategies to prevent ADAM17 activation and the development of resistant HTN.

在美国 55 岁及以上人群中，高血压 (HTN) 的患病率高达 55% 导致心血管疾病（CVD）和全球死亡率的主要危险因素，因此仍然是 日益重要的医疗和公共卫生问题。脑肾素-血管紧张素系统（RAS）在脑中的作用 维持正常血压 (BP) 以及导致高血压的神经心血管失调 已经牢固地确立了。血管紧张素 (Ang)-II 通过其 1 型受体 (AT1R) 促进 交感神经活动、盐和水重吸收、血管收缩、醛固酮和加压素释放 和炎症，这些都会导致高血压。虽然我们小组和其他人进行了大量的过度表达研究， 已确定 ACE2（2 型血管紧张素转换酶）在预防进展方面的益处 并在实验模型中改进 HTN 的治疗，我们的小组是第一个证明 ADAM17 （一种解整合素和金属蛋白酶）介导神经源性 HTN 中 ACE2 的脱落，从而减少 ACE2 小鼠和人类的补偿活动。 ADAM17 介导的 ACE2 脱落，这是蛋白质 胞外域从质膜上裂解并分泌到周围环境中，此后被 在包括心脏和肾脏在内的许多组织中得到证实。 ADAM17 被认为通过介导神经炎症 可溶性 TNFα、IL-6 反式信号传导、CX3CL1 等细胞因子，但这一机制尚未在国内外研究 神经源性高血压。 DOCA-盐 HTN 与 TNFα、IL-6 水平升高和 ACE2 活性降低相关 在大脑中，从神经元中删除 ADAM17 会降低血压，恢复 ACE2 活性并降低亲 炎症细胞因子。尽管 ADAM17 被认为是炎症的主要药物靶点， 选择性抑制剂的开发失败了。最近的工作被认为是革命性的，表明 ADAM17 成熟受到大脑中菱形蛋白（神经元中的 iRhom1 和小胶质细胞中的 iRhom2）的严格调节， 为新颖的目标策略打开了大门。因此，我们假设针对 ADAM17 成熟 将逆转神经源性高血压的交感神经兴奋和神经炎症。我们将测试这个新的 战略目标有以下两个具体目标。 使用人类干细胞衍生的神经元和小胶质细胞的组合，独特的转基因和条件 敲除小鼠，选择性删除小胶质细胞中的 ADAM17 (Cx3Cr1ERT2-ADAM17tom) 并靶向 敲低神经元 (Rhom1) 或小胶质细胞 (iRhom2) 中 ADAM17 的成熟，这是该研究的直接目标 应用程序的目的是： 1) 了解 ADAM17 上调是如何在整个前交感神经网络中发生的； 2）评估ADAM17在神经炎症和小胶质细胞激活中的前馈作用； 3) 测试新的 防止 ADAM17 激活和耐药 HTN 发展的临床相关靶向策略。