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：
10090670
负责人：
Hülya Bayir
金额：
$ 57.31万
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/10090670
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 Microscopy Mitochondria Mitochondrial DNA Modeling Motor NADH Necrosis Nerve Degeneration Neurological outcome Neurons Nuclear Organism Outcome Oxygen Pathogenesis Pharmaceutical Preparations Placebos Poly Adenosine Diphosphate Ribose Poly(ADP-ribose) Polymerases Polymers Quality of life Randomized Rattus Reactive Oxygen Species Regimen Reporting Research Resolution Role Septic Shock Shock Source Status Epilepticus Stroke Structure-Activity Relationship Therapeutic Time Traumatic Brain Injury Western Blotting age related apoptosis inducing factor base cognitive testing deprivation druggable target improved in vivo in vivo imaging infancy inhibitor/antagonist lipidomics liquid chromatography mass spectrometry male metabolic rate nanomolar neonatal hypoxic-ischemic brain injury neuroinflammation neuron loss neuroprotection novel preservation prevent release factor severe injury sex survivorship targeted treatment tool

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.

脑损伤后的生存质量是目前危重或受伤婴儿面临的最大挑战限制儿童生存质量的一个普遍因素是缺氧缺血的破坏性影响。脑病 (HIE)，作为心脏骤停、中风或颅内出血病例的主要后果出血或癫痫持续状态、循环性休克或感染性休克情况下的继发性后遗症，神经炎症或创伤性脑损伤 (TBI)，是婴儿期 HIE 的主要原因；青春期时心脏骤停导致的 HIE 迄今为止尚未找到治愈方法。范式转变策略对于改善 HIE 受害者的神经系统结果可能是必要的。因此，我们开发了一种新的疗法，通过保留关键的 HIE 来治疗 HIE。通过选择性靶向线粒体 (mtPARP) 中的聚 (ADP-核糖) 聚合酶 (PARP) 来储存细胞能量，将线粒体靶向部分半短杆菌肽 S (XJB) 或三苯基膦 (TPP) 连接到 PARP 临床上使用的抑制剂，由 DNA 损伤引发的缺血引起的 PARP 过度激活会消耗 NAD+，生成支链聚（ADP-核糖）聚合物（PARylation），导致 ATP 耗尽、能量衰竭，以及由坏死和/或凋亡诱导因子（AIF）介导的死亡细胞，如线粒体。需氧生物中 ATP 和 NAD+ 的主要来源，保存线粒体能量储存代表了缓解 HIE 的逻辑“可药物”目标。我们最近报道称，线粒体- 靶向 PARP1 抑制剂 XJB-veliparib 保留 NAD+ 储存并防止缺氧后神经元死亡重要的是，XJB-veliparib 选择性靶向体外葡萄糖剥夺 (OGD)。线粒体，因此不会阻碍体外核 DNA 修复。表明 XJB-veliparib 和易于翻译的线粒体靶向化合物 TPP-veliparib 可能在出生后 (PND) 17 只大鼠（发育年龄相当于幼鼠）中心脏骤停后有效儿童和脑代谢高峰期这一新疗法具有优势。通过选择性靶向 mtPARP 来预防 PARP 介导的能量衰竭和细胞死亡 PARP1 促进核 DNA 修复，并提供明确建立（或反驳）mtPARP 作用的工具在 HIE 的发病机制中。如果被证明有效，mtPARP1 抑制剂将代表新颖、安全（就核 DNA 修复而言）、以及缓解 HIE 的可转化疗法，对高度脆弱、发育中的大脑具有特殊潜力新陈代谢率达到峰值的地方。