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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

基本信息

批准号：
10669034
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
项目类别：
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/10669034
关键词：
Acute Address Adverse effects Animal Model Autoimmune Diseases Binding Binding Sites Blood Pressure Brain Calcineurin Calcineurin inhibitor Cells Central Nervous System 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 Neuronal Plasticity Neurons Organ Transplantation Output Pathogenesis Patients Pharmaceutical Preparations Phosphoric Monoester Hydrolases Phosphorylation Play Proteins Rattus Regulation Resistant Hypertension Rheumatoid Arthritis Role Secondary Hypertension Serine Sodium Source Spinal Sympathetic Nervous System Synapses Synaptic Receptors Synaptic plasticity System T-Lymphocyte Tacrolimus Testing Therapeutic Agents Threonine Vasomotor Vertebral column Work blood pressure elevation blood pressure reduction blood pressure regulation clinically relevant design experimental study hypertensive in vivo innovation mortality neural neuromechanism painful neuropathy paraventricular nucleus postsynaptic presynaptic trafficking transplantation medicine vasoconstriction

项目摘要

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.

钙调神经磷酸酶抑制剂致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枢交感神经系统是如何参与钙调神经磷酸酶抑制剂引起的高血压(CIH)。钙调神经磷酸酶抑制剂，包括环孢素和他克莫司 (FK506)，使移植医学发生了革命性的变化，大大延长了移植物的存活时间。然而，坚持不懈高血压仍然是长期使用钙调神经磷酸酶抑制剂的主要不良反应。虽然钙调神经磷酸酶抑制剂可以增加交感神经的活性，起到中枢交感神经的作用制度在CIH的发展中被很大程度上忽视了。此外，之前关于神经机制的工作 CIH的研究重点是单次注射钙调神经磷酸酶抑制剂的急性效应。目前尚不清楚地点和地点 CIH中增加的交感神经流出是如何在大脑中产生的。下丘脑室旁核核团(PVN)在高血压的发病机制中起重要作用，钙调神经磷酸酶(CaN)含量丰富在室旁核中表达。最近的研究表明，α-2δ-1可以直接调节谷氨酸受体中枢神经系统(NMDAR)活动。我们的初步研究表明，长期治疗 FK506诱导的动脉血压逐渐持续升高，甚至持续了很多天在FK506停产后。此外，阻断NMDAR或抑制α2δ-1-NMDAR复合体在经FK506治疗后，PVN可显著降低血压和增加交感神经放电。根据我们强大的初步数据，我们建议检验延长治疗的总体假设钙调神经磷酸酶抑制剂通过增强NMDAR增加对PVN前交感神经元的谷氨酸能输入磷酸化和α2δ-1介导的突触NMDAR活性，导致交感神经持续增加外流和高血压。我们将使用几种创新的体外和体内方法来定义持久性神经可塑性涉及分子、细胞和系统水平的脑出血。我们建议的研究可望解开交感血管运动持续增加的细胞和分子底物在CIH的活动。这一新信息将极大地增加我们对脑出血神经机制的理解。并使设计治疗这种情况的新策略成为可能。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Calcineurin inhibition causes persistent hypertension through hypothalamic NMDA receptor-dependent sympathetic outflow.

钙调神经磷酸酶抑制通过下丘脑 NMDA 受体依赖性交感神经流出导致持续性高血压。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Zhou,Jing-Jing;Shao,Jian-Ying;Chen,Shao-Rui;Pan,Hui-Lin
通讯作者：
Pan,Hui-Lin

α2δ-1-Dependent NMDA Receptor Activity in the Hypothalamus Is an Effector of Genetic-Environment Interactions That Drive Persistent Hypertension.

下丘脑中α2α-1 依赖性NMDA 受体活性是驱动持续性高血压的遗传环境相互作用的效应器。

DOI：
10.1523/jneurosci.0346-21.2021
发表时间：
2021
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Zhou,Jing-Jing;Shao,Jian-Ying;Chen,Shao-Rui;Li,De-Pei;Pan,Hui-Lin
通讯作者：
Pan,Hui-Lin

DNA demethylation in the hypothalamus promotes transcription of Agtr1a and Slc12a2 and hypertension development.