Cyclophilin D as a Therapeutic Target following Traumatic Brain Injury

亲环蛋白 D 作为创伤性脑损伤后的治疗靶点

基本信息

批准号：
8091240
负责人：
James W. Geddes
金额：
$ 31.83万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8091240
关键词：
Abbreviations Adenine Nucleotide Translocase Adenine Nucleotides Affinity Amino Acids Animal Model Astrocytes Attenuated Binding Binding Proteins Blood - brain barrier anatomy Brain Injuries Calcineurin Calcium Calpain Caspase Cell Death Cessation of life Chemical Structure Cleaved cell Clinical Clinical Trials Cyclophilin A Cyclophilins Cyclosporine Cyclosporins Cytosol Dose Endoplasmic Reticulum Event Exhibits Functional disorder Generic Drugs Genes Genetic Goals Health Healthcare Heterozygote Hydrogen Peroxide Immunosuppressive Agents In Vitro Injury Inner mitochondrial membrane Intervention Isoleucine Knockout Mice Lead Link Liver Mitochondria Membrane Potentials Mitochondria Mitochondrial Matrix Mitochondrial Proteins Mitochondrial Swelling Modeling Morbidity - disease rate Mus N-Methylaspartate Names Neuroglia Neuronal Injury Neurons Nomenclature Outcome Oxidative Stress Peptidylprolyl Isomerase Performance Permeability Pharmaceutical Preparations Pharmacological Treatment Proteins Rattus Reactive Oxygen Species Research Specificity Staging Synapses Synaptosomes Testing Tissues Toxic effect Traumatic Brain Injury United States Wallerian Degeneration analog apoptosis inducing factor base calcium green cis-trans-Isomerases controlled cortical impact cyclophilin D endonuclease G functional outcomes improved in vivo inhibitor/antagonist leucine methyl ester mitochondrial dysfunction mitochondrial membrane mitochondrial permeability transition pore neuron loss novel response solute therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The goal of this research is to minimize the secondary cell death and resultant morbidity following traumatic brain injury (TBI). Clinical interventions to improve outcome following TBI are extremely limited. Mitochondrial dysfunction is a pivotal link in the neuropathological sequalae of traumatic brain injury (TBI). TBI-induced increases in mitochondrial Ca2+ cycling/overload ultimately lead to opening of the mitochondrial permeability transition pore (mPTP). This pore, located on the inner mitochondrial membrane, opens in response to elevated Ca2+ and oxidative stress, and is gated by the mitochondrial protein cyclophilin D (CypD). When prolonged, mPTP opening is catastrophic as a result of the loss of mitochondrial membrane potential, and the release of calcium and death-related proteins from mitochondria. The goal of this research is to minimize the secondary cell death and resultant morbidity following TBI by limiting mPTP opening. The immunosuppressant Cyclosporin A (CsA) inhibits mPTP opening by binding to CypD. We and others previously demonstrated that CsA reduces the extent of tissue damage when administered following experimental TBI. Unfortunately, CsA is toxic at high concentrations, resulting from its inhibition of calcineurin. Recently we have demonstrated that CypD levels in primary neurons are approximately double the levels found in astrocytes and that CypD levels are also significantly higher in synaptic mitochondria (neuronal origin) compared to non-synaptic mitochondria (predominately non-neuronal origin). As a result of their high CypD content, we hypothesize that neuronal mitochondria are more vulnerable to mPTP opening and also require greater CsA levels to inhibit mPTP opening. To test this hypothesis we propose to use genetic and newer pharmacologic approaches to inhibit CypD following neuronal injury. Specifically, we will use CypD knockout mice and a CsA derivative, NIM811, which does not bind to or inhibit calcineurin. The specific aims are: 1: To evaluate the hypothesis that the high CypD content of neuronal mitochondria enhances vulnerability to mPTP opening following insults that result in elevated intracellular Ca2+ and oxidative stress. 2: To evaluate the hypothesis that the levels of the CypD inhibitor NIM811 required to protect neurons from excitotoxic insult is proportional to their CypD content. 3: To examine the hypothesis that mitochondrial CypD levels modulate the neuropathologic and functional outcome following TBI in mice. 4: To examine the hypothesis that CypD inhibitor NIM811 reduces tissue damage and improves functional outcome following TBI. Based on the results of these studies, we anticipate that NIM811 will exhibit strong potential as novel therapy for TBI. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a devastating healthcare problem in the United States, with no pharmacological treatments currently approved for clinical intervention following injury. Improved TBI treatment options are urgently needed. This proposal examines the potential of NIM811, a derivative of CsA, to limit the brain damage and dysfunction resulting from TBI.

描述（由申请人提供）：这项研究的目的是最大程度地减少创伤性脑损伤（TBI）后的次要细胞死亡和导致的发病率。 TBI后改善预后的临床干预措施极为有限。线粒体功能障碍是创伤性脑损伤（TBI）神经病理序列中的关键联系。 TBI诱导的线粒体Ca2+循环/超负荷的增加最终导致线粒体通透性过渡孔（MPTP）的打开。该孔位于线粒体内部膜上，响应于Ca2+升高和氧化应激而打开，并由线粒体蛋白环磷脂D（CYPD）门控。延长时，由于线粒体膜电位的丧失以及钙和死亡相关蛋白从线粒体的释放，MPTP开口是灾难性的。这项研究的目的是通过限制MPTP开放，最大程度地减少TBI后的次要细胞死亡和导致的发病率。免疫抑制剂环孢菌素A（CSA）通过与CYPD结合来抑制MPTP的开放。我们和其他人以前证明，在实验性TBI后给予CSA时，CSA会降低组织损伤的程度。不幸的是，CSA是由于钙调神经酶的抑制作用而在高浓度下具有毒性。最近，我们已经证明，原发性神经元中的CYPD水平大约是星形胶质细胞中发现的水平的两倍，而与非突触线粒体相比（主要非神经脱神经的起源），突触线粒体（神经元起源）的CYPD水平也明显更高。由于它们高CYPD含量，我们假设神经元线粒体更容易受到MPTP开放的影响，并且还需要更高的CSA水平来抑制MPTP的开放。为了检验这一假设，我们建议使用遗传和较新的药理学方法来抑制神经元损伤后的CYPD。具体而言，我们将使用CYPD基因敲除小鼠和CSA衍生物NIM811，它们不结合或抑制钙调蛋白。具体目的是：1：评估以下假设：神经元线粒体的高CYPD含量在侮辱后增强了对MPTP打开的脆弱性，从而导致细胞内Ca2+升高和氧化应激。 2：评估保护神经元免受兴奋性毒性损伤所需的CYPD抑制剂NIM811的水平与其CYPD含量成正比。 3：检验以下假设：小鼠TBI后TBI后线粒体CYPD水平调节神经病理和功能结果。 4：检查CYPD抑制剂NIM811减少组织损伤并改善TBI后功能结果的假设。根据这些研究的结果，我们预计NIM811将表现出强大的潜力作为TBI的新型治疗。公共卫生相关性：创伤性脑损伤（TBI）是美国毁灭性的医疗保健问题，当前未批准药理学治疗损伤后的临床干预。迫切需要改进的TBI治疗选择。该建议研究了CSA的衍生物NIM811的潜力，以限制TBI引起的脑损伤和功能障碍。