Neural Mechanisms of Calcineurin Inhibitor-Induced Hypertension

钙调神经磷酸酶抑制剂诱发高血压的神经机制

• 批准号: 10224340
• 负责人: Hui-Lin Pan
• 金额: $ 58.67万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224340
• 关键词: Acute; Address; Adverse effects; Animal Model; Autoimmune Diseases; Binding Sites; Blood Pressure; Brain; Calcineurin; Calcineurin inhibitor; Cells; Clinical; Complex; Cyclosporine; Data; Development; Elderly; Endocrine system; FK506; Functional disorder; Glutamates; Goals; Graft Survival; Hypertension; Hypothalamic structure; Immune system; Immunosuppressive Agents; In Vitro; Injections; Intervention; Kidney; Kidney Failure; Knowledge; Mediating; Molecular; N-Methyl-D-Aspartate Receptors; Nerve; Nervous system structure; Neuraxis; Neuronal Plasticity; Neurons; Organ Transplantation; Output; Pathogenesis; Patients; Pharmaceutical Preparations; Phosphorylation; Play; Protein Serine/Threonine Phosphatase; Proteins; Rattus; Regulation; Resistant Hypertension; Rheumatoid Arthritis; Role; Secondary Hypertension; Sodium; Source; Spinal; Sympathetic Nervous System; Synapses; Synaptic Receptors; Synaptic plasticity; System; T-Lymphocyte; Tacrolimus; Testing; Therapeutic Agents; Vasomotor; Work; blood pressure reduction; blood pressure regulation; clinically relevant; design; experimental study; in vivo; innovation; mortality; neuromechanism; painful neuropathy; paraventricular nucleus; postsynaptic; presynaptic; relating to nervous system; trafficking; transplantation medicine; vasoconstriction

Neural Mechanisms of Calcineurin Inhibitor-Induced Hypertension Project Summary The major goal of our project is to determine how the central sympathetic nervous system is involved in calcineurin inhibitor–induced hypertension (CIH). Calcineurin inhibitors, including cyclosporine and tacrolimus (FK506), have revolutionized transplant medicine and substantially prolonged graft survival. However, persistent hypertension remains a major adverse effect associated with long-term use of calcineurin inhibitors. Although calcineurin inhibitors can increase the sympathetic nerve activity, the role of the central sympathetic nervous system in the development of CIH has been largely overlooked. Also, previous work on the neural mechanisms of CIH has focused on the acute effect of a single injection of calcineurin inhibitors. It remains unclear where and how the augmented sympathetic outflow in CIH is generated in the brain. The hypothalamic paraventricular nucleus (PVN) plays an important role in the pathogenesis of hypertension, and calcineurin is abundantly expressed in the PVN. Recent studies indicate that α2δ-1 can directly regulate glutamate NMDA receptor (NMDAR) activity in the central nervous system. Our preliminary studies showed that long-term treatment with FK506 induced a gradual and sustained increase in arterial blood pressure, which persisted for many days even after FK506 was discontinued. Furthermore, blocking NMDARs or inhibiting the α2δ-1–NMDAR complex in the PVN profoundly reduced blood pressure and the sympathetic nerve discharges augmented by FK506 treatment. On the basis of our strong preliminary data, we propose to test the overall hypothesis that prolonged treatment with calcineurin inhibitors increases glutamatergic input to PVN presympathetic neurons by potentiating NMDAR phosphorylation and α2δ-1–mediated synaptic NMDAR activity, leading to a sustained increase in sympathetic outflow and hypertension. We will use several innovative in vitro and in vivo approaches to define the persistent neural plasticity involved in CIH at molecular, cellular, and system levels. Our proposed studies are expected to unravel the cellular and molecular substrates responsible for the sustained increase in sympathetic vasomotor activity in CIH. This new information will greatly increase our understanding of the neural mechanisms of CIH and enable the design of new strategies for treating this condition.

钙调神经酶抑制剂诱导的高血压的神经机制 项目摘要 我们项目的主要目标是确定中心同情神经系统如何参与 钙调神经酶抑制剂诱导的高血压（CIH）。钙调蛋白抑制剂，包括环孢菌素和他克莫司 （FK506）已彻底改变了移植药物，并大大延长了移植物生存。但是，持久 高血压仍然与长期使用钙调神经酶抑制剂有关的主要不利影响。虽然 钙调神经素抑制剂可以增加交感神经活动，这是中心交感神经的作用 CIH开发的系统在很大程度上被忽略了。此外，先前关于神经机制的工作 CIH的重点是单个注射钙调神经蛋白抑制剂的急性作用。目前尚不清楚哪里和 如何在大脑中产生CIH中的增强交感神经。下丘脑旁腔 核（PVN）在高血压的发病机理中起重要作用，钙调神经酶绝对 在PVN中表达。最近的研究表明，α2δ-1可以直接调节谷氨酸NMDA受体 （NMDAR）中枢神经系统的活性。我们的初步研究表明，长期治疗 FK506诱导了动脉血压的等级并持续增加，甚至持续了很多天 FK506停产后。此外，阻止NMDAR或抑制α2δ-1-NMDAR复合物 PVN严重降低了血压，通过FK506治疗增加了交感神经的神经出现。 根据我们强大的初步数据，我们建议测试延长治疗的总体假设 通过钙调神经磷酸酶抑制剂通过增强NMDAR，将谷氨酸能的输入增加到PVN的同情神经元 磷酸化和α2δ-1介导的突触NMDAR活性，导致交感神经持续增加 出口和高血压。我们将使用几种创新的体外和体内方法来定义持久性 在分子，细胞和系统水平上参与CIH的神经可塑性。我们建议的研究预计 揭示负责交感神经运动持续增加的细胞和分子底物 CIH的活动。这些新信息将大大增加我们对CIH神经机制的理解 并启用设计新策略的设计。