Targeting ADAM17 maturation in resistant hypertension.

靶向顽固性高血压中 ADAM17 的成熟。

• 批准号: 10608153
• 负责人: ERIC D LAZARTIGUES
• 金额: $ 54.93万
• 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/10608153
• 关键词: Affect; Age; Aldosterone; Angiotensin II; Angiotensins; Autonomic Dysfunction; 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; Glutamates; 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; absorption; aged; 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.

高血压(HTN)在美国55岁及以上人群中的患病率高达55%，是一种 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。脑内肾素-血管紧张素系统(RAS)在血管紧张素系统中的作用 正常血压的维持和导致HTN的神经-心血管失调 已经站稳了脚跟。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，都是HTN的致病因素。虽然来自我们团队和其他人的大量过度表达研究， 已经确定了ACE2(血管紧张素转换酶2型)在防止进展中的好处 并在实验模型上改进了HTN的治疗，我们小组首先证明了ADAM17 去整合素和金属蛋白水解酶介导神经源性HTN中ACE2的脱落，从而减少ACE2 老鼠和人类的代偿活动。ADAM17介导的ACE2脱落，蛋白质通过这个过程 胞外结构域从质膜上被切割并分泌到周围环境中，自那以后 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 可溶性肿瘤坏死因子α、IL-6反式信号转导、CX3CL1等细胞因子的作用机制尚未见文献报道。 神经源性HTN。DOCA-SALT HTN与肿瘤坏死因子α、IL-6水平升高和血管紧张素转换酶2活性降低相关 在大脑中，虽然从神经元中删除ADAM17会降低血压，恢复ACE2活性，并减少PRO-2 炎性细胞因子。尽管ADAM17被认为是治疗炎症的主要药物靶点，但 选择性抑制剂的开发已经失败。最近的研究，被认为是革命性的，表明ADAM17 成熟受到大脑中菱形蛋白的严格调控(神经元中的IRHOM1和小胶质细胞中的IRHOM2)， 为新的目标策略打开了大门。因此，我们假设靶向ADAM17成熟 将逆转神经源性HTN的交感兴奋和神经炎症。我们将测试这一新的 目标定位策略有以下两个具体目标。 使用人类干细胞来源的神经元和小胶质细胞的组合，独特的转基因和有条件的 小胶质细胞ADAM17选择性缺失基因敲除小鼠(Cx3Cr1ERT2-ADAM17tom)并靶向 抑制ADAM17在神经元(Rhom1)或小胶质细胞(IRHOM2)中的成熟，这是这一研究的直接目标 应用是为了：1)了解ADAM17上调是如何在交感前网络中发生的； 2)评估ADAM17在神经炎症和小胶质细胞激活中的前馈作用；以及3)测试新的 临床相关的靶向策略，以防止ADAM17激活和耐药HTN的发展。