Druggable Mitochondrial Targets for Treatment of Cerebral Ischemia

用于治疗脑缺血的可药物线粒体靶点

基本信息

批准号：
10592289
负责人：
Hülya Bayir
金额：
$ 56.93万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2020-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10592289
关键词：
Adolescence Aerobic Aftercare Age Antioxidants Brain Brain Injuries Brain region Cell Death Cell Death Signaling Process Cell Respiration Cerebral Ischemia Cerebral Ischemia-Hypoxia Cerebrum Child Childhood Clinical Computer Models Consumption Critical Illness DNA Damage DNA Repair Data Development Dose Event Failure Female Generations Glucose Gramicidin S Heart Arrest Histologic Image In Vitro Infant Injury Intracranial Hemorrhages Ischemia Link Mediating Metabolism Mitochondria Mitochondrial DNA Modeling Motor NADH Necrosis Nerve Degeneration Neurological outcome Nuclear Organism Outcome Oxygen Pathogenesis Pharmaceutical Preparations Placebos Poly Adenosine Diphosphate Ribose Poly(ADP-ribose) Polymerase Inhibitor Poly(ADP-ribose) Polymerases Polymers Quality of life Randomized Rattus Reactive Oxygen Species Regimen Reporting Research Role Septic Shock Shock Source Status Epilepticus Stroke Structure-Activity Relationship Therapeutic Time Traumatic Brain Injury Western Blotting age related apoptosis inducing factor cognitive testing deprivation druggable target improved in vivo in vivo imaging infancy inhibitor lipidomics liquid chromatography mass spectrometry male metabolic rate nanomolar neonatal hypoxic-ischemic brain injury neuroinflammation neuron loss neuronal survival neuroprotection novel postnatal preservation prevent release factor severe injury sex superresolution microscopy survivorship targeted treatment tool translational potential

项目摘要

Quality survival after brain injury is currently the greatest challenge for critically ill or injured infants and children. A universal contributor limiting quality survivorship is the devastating impact of hypoxic-ischemic encephalopathy (HIE), either as a primary consequence in cases of cardiac arrest, stroke, or intracranial hemorrhage or as secondary sequelae in cases of status epilepticus, circulatory or septic shock, neuroinflammation, or traumatic brain injury (TBI); with the principal cause of HIE spanning from infancy through adolescence a consequence of cardiac arrest. As to-date a cure for HIE has not been discovered, a paradigm-shifting strategy is likely necessary to improve neurological outcome for victims of HIE. Accordingly, we have developed a new class of therapeutics to treat HIE via preservation of critical cellular energy stores by selectively targeting poly(ADP-ribose) polymerase (PARP) in mitochondria (mtPARP), linking the mitochondria-targeting moieties hemi-gramicidin S (XJB) or triphenylphosphonium (TPP) to PARP inhibitors used clinically. Ischemia-induced PARP overactivation triggered by DNA damage consumes NAD+, generating branch chain poly(ADP-ribose) polymers (PARylation) resulting in ATP depletion, energy failure, and cell death by necrosis and/or apoptosis-inducing factor (AIF)-mediated parthanatos. As mitochondria are the major source of ATP and NAD+ in aerobic organisms, preservation of mitochondrial energy stores represents a logical “druggable” target for mitigation of HIE. We recently reported that the mitochondria- targeting PARP1 inhibitor XJB-veliparib preserves NAD+ stores and prevents neuronal death after oxygen- glucose deprivation (OGD) in vitro at nanomolar concentrations. Importantly, XJB-veliparib selectively targets mitochondria and thereby does not impede nuclear DNA repair in vitro. We present provocative pilot data suggesting that XJB-veliparib and the readily translatable mitochondria-targeting compound TPP-veliparib may be efficacious after cardiac arrest in post-natal day (PND) 17 rats, a developmental age equivalent to a young child and a time associated with peak cerebral metabolism. This new class of therapeutics has the advantage of preventing PARP-mediated energy failure and cell death by selectively targeting mtPARP while sparing PARP1-facilitated nuclear DNA repair and provide a tool to definitively establish (or refute) a role for mtPARP in the pathogenesis of HIE. If proven effective, mtPARP1 inhibitors would represent novel, safe (in terms of nuclear DNA repair), and translatable therapies to mitigate HIE, with special potential in the highly vulnerable, developing brain where metabolic rate is at its peak.

脑损伤后的质量生存是目前对重病或受伤的婴儿的最大挑战孩子们。限制质量生存的普遍贡献者是缺氧缺血的毁灭性影响脑病（HIE）是心脏骤停，中风或颅内的主要结果在癫痫持续性，回路或化粪池休克的情况下出血或继发性后遗症，神经炎症或创伤性脑损伤（TBI）；与婴儿期有关的主要原因通过青少年的心脏骤停后果。因为尚未发现待会的治疗方法，所以改善HIE的神经系统效果可能需要进行范式转移策略。彼此之间，我们已经开发了一种新的治疗方法来通过保存关键通过选择性靶向线粒体（MTPARP）中的聚（ADP-核糖）聚合酶（PARP）的细胞能量储存将靶向线粒体靶向部分的Hemi-gramIcidin S（XJB）或Triphenylphosphonium（TPP）连接到PARP 临床上使用的抑制剂。由DNA损伤触发的缺血诱导的PAR过度活化会消耗NAD+，产生分支链聚（ADP-核糖）聚合物（parylation），导致ATP部署，能量故障，坏死和/或细胞凋亡诱导因子（AIF）介导的parthanatos死亡。如线粒体有氧生物中ATP和NAD+的主要来源，线粒体能量储存的保存代表了缓解HIE的逻辑“可药”目标。我们最近报道了线粒体 - 靶向PARP1抑制剂XJB-veliparib可保留NAD+存储，并防止氧气后神经元死亡在纳摩尔浓度下的体外葡萄糖剥夺（OGD）。重要的是，XJB-Veliparib有选择地目标线粒体，因此不会阻碍体外的核DNA修复。我们提出挑衅性的飞行员数据建议XJB-Veliparib和易于翻译的线粒体靶向复合TPP-Veliparib可能在产后日（PND）17只大鼠心脏骤停后效率，这是一个相当于年轻人的发育年龄儿童和与大脑峰值代谢相关的时间。这种新的疗法具有优势通过选择性靶向MTPARP，预防PARP介导的能量失效和细胞死亡 PARP1采用核DNA修复，并提供一种工具来确定（或驳斥）MTPARP的作用在Hie的发病机理中。如果证明有效，MTPARP1抑制剂将代表新颖的安全（在核DNA修复方面），并翻译疗法以减轻Hie，在高度脆弱的大脑中具有特殊潜力代谢率达到顶峰的地方。