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

• 批准号: 8286331
• 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
• 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/8286331
• 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

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）：本研究的目的是尽量减少创伤性脑损伤（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）神经病理学后遗症的关键环节。TBI诱导的线粒体Ca 2+循环/过载的增加最终导致线粒体通透性转换孔（mPTP）的开放。这个位于线粒体内膜上的孔会响应升高的Ca 2+和氧化应激而打开，并由线粒体蛋白亲环素D（CypD）门控。当延长时，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开放是灾难性的。本研究的目的是通过限制mPTP开放来最小化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开放。我们和其他人以前证明，CsA减少组织损伤的程度时，管理后实验性TBI。不幸的是，CsA在高浓度下是有毒的，这是由于其抑制钙调磷酸酶。最近，我们已经证明，原代神经元中的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（主要是非神经元来源）相比，突触线粒体（神经元来源）中的CypD水平也显著更高。由于它们的高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开放。为了验证这一假设，我们建议使用遗传和更新的药理学方法来抑制CypD神经元损伤。具体来说，我们将使用CypD基因敲除小鼠和CsA衍生物NIM 811，它不结合或抑制钙调磷酸酶。具体目标是：一曰：评估神经元线粒体的高CypD含量增强了损伤后mPTP开放的脆弱性，导致细胞内Ca 2+和氧化应激升高的假设。第二章：为了评估保护神经元免受兴奋性毒性损伤所需的CypD抑制剂NIM 811的水平与其CypD含量成比例的假设。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。4：检验CypD抑制剂NIM 811减少TBI后的组织损伤并改善功能结果的假设。基于这些研究的结果，我们预计NIM 811将显示出强大的潜力作为TBI的新疗法。公共卫生相关性：创伤性脑损伤（TBI）在美国是一个毁灭性的医疗保健问题，目前没有药物治疗被批准用于损伤后的临床干预。迫切需要改进TBI治疗方案。该提案研究了NIM 811（CsA的衍生物）限制TBI引起的脑损伤和功能障碍的潜力。