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：
8499435
负责人：
James W. Geddes
金额：
$ 30.72万
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 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8499435
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 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 public health relevance 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.

描述（由申请人提供）：本研究的目标是最大限度地减少创伤性脑损伤（TBI）后的继发性细胞死亡和由此产生的发病率。改善 TBI 后预后的临床干预措施极其有限。线粒体功能障碍是脑外伤（TBI）神经病理后遗症的关键环节。 TBI 诱导的线粒体 Ca2+ 循环/过载增加最终导致线粒体通透性转换孔 (mPTP) 打开。该孔位于线粒体内膜上，响应 Ca2+ 升高和氧化应激而打开，并由线粒体蛋白亲环蛋白 D (CypD) 控制。当时间延长时，由于线粒体膜电位的丧失以及线粒体中钙和死亡相关蛋白的释放，mPTP 打开是灾难性的。本研究的目标是通过限制 mPTP 开放来最大限度地减少 TBI 后的继发性细胞死亡和由此产生的发病率。免疫抑制剂环孢菌素 A (CsA) 通过与 CypD 结合来抑制 mPTP 打开。我们和其他人之前证明，在实验性 TBI 后施用 CsA 可以减少组织损伤的程度。不幸的是，CsA 在高浓度下具有毒性，这是由于它抑制钙调神经磷酸酶。最近我们证明，初级神经元中的 CypD 水平大约是星形胶质细胞中发现的水平的两倍，并且与非突触线粒体（主要是非神经元起源）相比，突触线粒体（神经元起源）中的 CypD 水平也显着更高。由于 CypD 含量高，我们假设神经元线粒体更容易受到 mPTP 打开的影响，并且还需要更高的 CsA 水平来抑制 mPTP 打开。为了检验这一假设，我们建议使用遗传和更新的药理学方法来抑制神经元损伤后的 CypD。具体来说，我们将使用 CypD 敲除小鼠和 CsA 衍生物 NIM811，它不会结合或抑制钙调神经磷酸酶。具体目标是： 1：评估以下假设：神经元线粒体的高 CypD 含量会增强在导致细胞内 Ca2+ 升高和氧化应激的损伤后对 mPTP 打开的脆弱性。图 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 水平与其 CypD 含量成正比的假设。图 3：检验线粒体 CypD 水平调节小鼠 TBI 后的神经病理学和功能结果的假设。图 4：检验 CypD 抑制剂 NIM811 减少 TBI 后组织损伤并改善功能结果的假设。根据这些研究结果，我们预计 NIM811 将展现出作为 TBI 新型疗法的强大潜力。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Concentration dependent effect of calcium on brain mitochondrial bioenergetics and oxidative stress parameters.

钙对脑线粒体生物能学和氧化应激参数的浓度依赖性影响。

DOI：
发表时间：
2013
期刊：
影响因子：
0
作者：
Pandya, Jignesh D;Nukala, Vidya N;Sullivan, Patrick G
通讯作者：
Sullivan, Patrick G

Age- and brain region-specific differences in mitochondrial bioenergetics in Brown Norway rats.

棕色挪威大鼠线粒体生物能学的年龄和大脑区域特异性差异。

DOI：
发表时间：
2016-06
期刊：
影响因子：
4.2
作者：
Pandya, Jignesh D;Royland, Joyce E;MacPhail, Robert C;Sullivan, Patrick G;Kodavanti, Prasada Rao S
通讯作者：
Kodavanti, Prasada Rao S

Antioxidant properties of Neu2000 on mitochondrial free radicals and oxidative damage.

Neu2000 对线粒体自由基和氧化损伤的抗氧化特性。

DOI：
10.1016/j.tiv.2012.12.011
发表时间：
2013-03-01
期刊：
Toxicology in vitro : an international journal published in association with BIBRA
影响因子：
0
作者：
Nishant P Visavadiya;M. Mcewen;Jignesh D. P;ya;ya;P. Sullivan;B. Gwag;J. Springer
通讯作者：
J. Springer

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James W. Geddes其他文献

Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease

Par-4 是与阿尔茨海默病发病机制相关的神经元变性的介质

DOI：
发表时间：
1998
期刊：
Nature Network Boston
影响因子：
0
作者：
Q. Guo;Weiming Fu;Jun Xie;Hong Luo;S. Sells;James W. Geddes;Vimala Bondada;V. Rangnekar;M. Mattson
通讯作者：
M. Mattson