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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.

脑损伤后的高质量生存是目前危重或受伤婴儿面临的最大挑战