The Permeability Transition in Hepatic Encephalopathy

肝性脑病的渗透性转变

基本信息

批准号：
7284854
负责人：
MICHAEL David NORENBERG
金额：
$ 26.28万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-01 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7284854
关键词：
2-deoxyglucose-6-phosphate 5,5&apos ,6,6&apos -tetrachloro-1,1&apos ,3,3&apos -tetraethylbenzimidazolocarbocyanine Acetates Acids Acute Acute Liver Failure Alcar Alzheimer&apos s Disease Ammonia Animal Model Appendix Astrocytes Bioenergetics Brain Edema Calcium Carnitine Cells Cerebrum Clinical Coenzymes Complex Condition Creatine Cyclosporine Data Defect Development Disease Due Process Emergency Situation Energy Metabolism Esters Experimental Models Failure Functional disorder Glutamate-Ammonia Ligase Glutamates Glutamine Glutathione Disulfide Hepatic Encephalopathy Hyperammonemia In Vitro Injury Inner mitochondrial membrane Iodides Levocarnitine Acetyl Liver Failure Malate-Aspartate Shuttle Pathway Mediating Membrane Potentials Methionine Sulfoximine Mitochondria Monoamine Oxidase Morbidity - disease rate NOS1 protein, human Neurons Neurotoxins Niacinamide Nitric Oxide Nitric Oxide Synthase Numbers Outcome Oxidative Stress Pathogenesis Pathway interactions Patients Perchloric Acids Permeability Phosphate Buffer Phosphocreatine Play Procedures Production Propane Reactive Oxygen Species Reduced Glutathione Relative (related person)Research Personnel Respiratory Chain Role Saline Solutions Sulfonic Acids Superoxide Dismutase Swelling Testing Thinking Toxic effect Trifluoperazine Work base cell injury concept human NOS3 protein improved in vivo in vivo Model inhibitor/antagonist liver transplantation mitochondrial dysfunction mitochondrial membrane mortality neurochemistry neurotoxicity neurotransmitter uptake novel therapeutics outcome forecast oxophenylarsine prevent programs respiratory response salt balance tert-Butylhydroperoxide tetramethylrhodamine uptake

项目摘要

DESCRIPTION (provided by applicant): Hepatic encephalopathy (HE) is an important cause of morbidity and mortality in patients with severe liver failure. Acute HE associated with fulminant hepatic failure has an extremely poor prognosis and specific therapy is not available, short of an emergency liver transplantation. Although its pathogenesis remains poorly understood, ammonia is strongly implicated as a neurotoxin, and astrocytes appear to be the primary target of ammonia neurotoxicity. Additionally, altered bioenergetics and oxidative stress are thought to play a major role in this disorder. These facts led to a consideration of the involvement of mitochondrial permeability transition (MPT) as a factor in the pathogenesis of HE and ammonia neurotoxicity. The MPT is a Ca2+-dependent, cyclosporin A (CsA)-sensitive process due to the opening of a pore in the inner mitochondrial membrane leading to a collapse of ionic gradients and ultimately to mitochondrial dysfunction. We have recently shown that ammonia induced the MPT in cultured astrocytes. We intend to examine the role of the MPT in HE and hyperammonemia using ammonia-treated neural cell cultures and in vivo models of HE/hyperammonemia (HA). Our working hypothesis is that ammonia induces the MPT in astrocytes, culminating in mitochondrial failure and astroglial dysfunction. A corollary of this concept is that inhibition or interference in the development of the MPT in astrocytes may ameliorate CNS dysfunction in HE. The Specific Aims of this proposal are: 1) To identify the factors responsible for the ammonia-induced MPT in cultured neural cells. Our focus will be on agents implicated in the pathogenesis of HE/H that have also been shown to induce the MPT in other cells. Specifically, we will examine the role of Ca 2+, reactive oxygen species, nitric oxide, pH and glutamine. We will determine whether these factors are elevated in ammonia-treated cultures, and whether diminishing their production or blocking their actions reduces or abolishes the MPT. Additionally, we will examine possible sequential interrelationships among these factors. 2) To determine whether ammonia-induced abnormalities in astrocytes (morphological alterations, defects in neurotransmitter uptake, and cell swelling) are mediated by the MPT, we will investigate whether inhibitors of the MPT (CsA, bongkrekik acid) are capable of diminishing or blocking the deleterious effects of ammonia. 3) To investigate the involvement of mitochondrial dysfunction as a potential factor in MPT-mediated cell injury. We will determine the state of mitochondrial function after ammonia treatment, and then investigate whether improving energy metabolism will inhibit ammonia-induced cellular injury. 4) To clarify whether the MPT occurs in in vivo models of HE (thioacetarnide treatment) and hyperammonemia. We will also determine whether factors that inhibit the MPT in vitro (e.g., CsA, trifluoperazine) are also capable of doing so in vivo. Additionally, we will assess the ability of MPT blockers to improve the clinical, histopathologic, neurochemical abnormalities, and the extent of brain swelling observed in HE/HA. We believe that these studies will yield critical data bearing on the pathogenesis of HE, and may potentially aid in the development of novel therapeutic strategies for the treatment of this condition.

描述（由申请人提供）：肝性脑病（HE）是严重肝功能衰竭患者发病和死亡的重要原因。与暴发性肝衰竭相关的急性 HE 预后极差，除了紧急肝移植外，没有特异性治疗方法。尽管其发病机制仍知之甚少，但氨作为一种神经毒素密切相关，而星形胶质细胞似乎是氨神经毒性的主要目标。此外，生物能学和氧化应激的改变被认为在这种疾病中发挥着重要作用。这些事实导致人们考虑线粒体通透性转变 (MPT) 是 HE 和氨神经毒性发病机制中的一个因素。 MPT 是一种 Ca2+ 依赖性、环孢菌素 A (CsA) 敏感过程，因为线粒体内膜上的孔打开导致离子梯度崩溃，最终导致线粒体功能障碍。我们最近发现氨诱导培养的星形胶质细胞发生 MPT。我们打算使用氨处理的神经细胞培养物和 HE/高氨血症 (HA) 体内模型来研究 MPT 在 HE 和高氨血症中的作用。我们的工作假设是，氨会诱导星形胶质细胞发生 MPT，最终导致线粒体衰竭和星形胶质细胞功能障碍。这一概念的推论是，抑制或干扰星形胶质细胞中 MPT 的发育可能会改善 HE 中的 CNS 功能障碍。该提案的具体目标是： 1) 确定培养神经细胞中氨诱导 MPT 的影响因素。我们的重点将是与 HE/H 发病机制有关的药物，这些药物也已被证明可以在其他细胞中诱导 MPT。具体来说，我们将检查 Ca 2+、活性氧、一氧化氮、pH 值和谷氨酰胺的作用。我们将确定这些因素在经氨处理的培养物中是否升高，以及减少其产生或阻止其作用是否会减少或消除 MPT。此外，我们将检查这些因素之间可能存在的顺序相互关系。 2) 为了确定氨诱导的星形胶质细胞异常（形态改变、神经递质摄取缺陷和细胞肿胀）是否由 MPT 介导，我们将研究 MPT 抑制剂（CsA、bongkrekik 酸）是否能够减少或阻断氨的有害影响。 3) 研究线粒体功能障碍作为 MPT 介导的细胞损伤的潜在因素。我们将确定氨处理后线粒体功能的状态，然后研究改善能量代谢是否会抑制氨诱导的细胞损伤。 4) 阐明MPT是否发生在HE（硫代乙脒治疗）和高氨血症的体内模型中。我们还将确定体外抑制 MPT 的因子（例如 CsA、三氟拉嗪）是否也能够在体内发挥作用。此外，我们将评估 MPT 阻滞剂改善 HE/HA 中观察到的临床、组织病理学、神经化学异常和脑肿胀程度的能力。我们相信，这些研究将产生有关 HE 发病机制的关键数据，并可能有助于开发治疗这种疾病的新治疗策略。