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:
  • 金额:
    $ 56.93万
  • 依托单位:
  • 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

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

项目成果

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Hülya Bayir其他文献

Hülya Bayir的其他文献

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{{ truncateString('Hülya Bayir', 18)}}的其他基金

Radiation Mitigators Targeting Regulated Necrosis Pathways of Parthanatos Pyroptosis
针对帕塔纳托细胞焦亡的调节性坏死途径的辐射缓解剂
  • 批准号:
    10838232
  • 财政年份:
    2023
  • 资助金额:
    $ 56.93万
  • 项目类别:
Oxidative Lipidomics in Pediatric Traumatic Brain Injury
氧化脂质组学在小儿创伤性脑损伤中的应用
  • 批准号:
    10844023
  • 财政年份:
    2023
  • 资助金额:
    $ 56.93万
  • 项目类别:
Radiation Mitigators Targeting Regulated Necrosis Pathways of Parthanatos Pyroptosis
针对帕塔纳托细胞焦亡调节坏死途径的辐射缓解剂
  • 批准号:
    10436895
  • 财政年份:
    2020
  • 资助金额:
    $ 56.93万
  • 项目类别:
Radiation Mitigators Targeting Regulated Necrosis Pathways of Parthanatos Pyroptosis
针对帕塔纳托细胞焦亡调节坏死途径的辐射缓解剂
  • 批准号:
    10625932
  • 财政年份:
    2020
  • 资助金额:
    $ 56.93万
  • 项目类别:
Druggable Mitochondrial Targets for Treatment of Cerebral Ischemia
用于治疗脑缺血的可药物线粒体靶点
  • 批准号:
    10090670
  • 财政年份:
    2020
  • 资助金额:
    $ 56.93万
  • 项目类别:
Druggable Mitochondrial Targets for Treatment of Cerebral Ischemia
用于治疗脑缺血的可药物线粒体靶点
  • 批准号:
    10328870
  • 财政年份:
    2020
  • 资助金额:
    $ 56.93万
  • 项目类别:
Radiation Mitigators Targeting Regulated Necrosis Pathways of Parthanatos Pyroptosis
针对帕塔纳托细胞焦亡调节坏死途径的辐射缓解剂
  • 批准号:
    10212243
  • 财政年份:
    2020
  • 资助金额:
    $ 56.93万
  • 项目类别:
Mitochondria-Targeted Redox Therapy for Cerebral Ischemia in the Developing Brain
线粒体靶向氧化还原疗法治疗发育中大脑缺血
  • 批准号:
    8820302
  • 财政年份:
    2014
  • 资助金额:
    $ 56.93万
  • 项目类别:
Mitochondria-Targeted Redox Therapy for Cerebral Ischemia in the Developing Brain
线粒体靶向氧化还原疗法治疗发育中大脑缺血
  • 批准号:
    9193104
  • 财政年份:
    2014
  • 资助金额:
    $ 56.93万
  • 项目类别:
Mitochondria-Targeted Redox Therapy for Cerebral Ischemia in the Developing Brain
线粒体靶向氧化还原疗法治疗发育中大脑缺血
  • 批准号:
    8994750
  • 财政年份:
    2014
  • 资助金额:
    $ 56.93万
  • 项目类别:

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