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.

在美国，55岁及以上的个体的患病率高达55％，高血压（HTN）是一个 导致心血管疾病（CVD）和全球死亡率的主要危险因素，因此 越来越重要的医疗和公共卫生问题。大脑肾素 - 血管紧张素系统（RAS）在 维持正常血压（BP）和在神经血管内的失调，导致HTN 首先建立。血管紧张素（ANG）-II通过其1型受体（AT1R）促进增加 交感神经活动，盐和水的吸收，血管收缩，醛固酮和加压素释放 和炎症，都为HTN做出了贡献。虽然来自我们小组和其他人的大量过表达研究，但 已经确定了ACE2（血管紧张素转化2型酶）的好处，以防止进展 并改善了实验模型中HTN的处理，我们的小组是第一个证明ADAM17的人 （崩解蛋白和金属蛋白酶）介导神经源HTN中的ACE2脱落，从而减少ACE2 小鼠和人类的补偿性活动。 ADAM17介导的ACE2脱落，蛋白质的过程 胞外域从质膜上裂开并分泌到周围的环境中，此后一直是 在包括心脏和肾脏在内的许多组织中得到证实。 ADAM17被认为可以通过 可溶性TNFα，IL-6反式信号，CX3CL1和其他细胞因子，但该机制尚未研究 神经源HTN。 DOCA-SALT HTN与TNFα，IL-6的水平升高和ACE2活性降低有关 在大脑中，虽然从神经元中删除ADAM17会减少BP，但恢复ACE2活性并下降 炎症细胞因子。尽管ADAM17被认为是炎症的主要药物靶标，但 选择性抑制剂的发展失败了。被认为革命性的最近工作表明ADAM17 大脑中的菱形蛋白（神经元中的IRHOM1和小胶质细胞中的IRHOM2）严格调节成熟 为新颖的目标策略打开大门。根据，我们假设靶向ADAM17成熟 在神经源HTN中，将反向交感神经和神经炎症。我们将测试这个新的 在以下两个具体目标中针对策略。 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，在小胶质细胞（CX3CR1ERT2-ADAM17TOM）中有选择性删除ADAM17并针对目标 ADAM17神经元（RHOM1）或小胶质细胞（IRHOM2）中的成熟的敲低，这是此目的的直接目标 应用是：1）了解ADAM17在整个同情的网络中如何进行上调； 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 临床上与临床相关的靶向策略，以防止ADAM17激活和抗性HTN的发展。