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
- 来源:
- 关键词:AdolescenceAerobicAftercareAgeAntioxidantsBrainBrain InjuriesBrain regionCell DeathCell Death Signaling ProcessCell RespirationCerebral IschemiaCerebral Ischemia-HypoxiaCerebrumChildChildhoodClinicalComputer ModelsConsumptionCritical IllnessDNA DamageDNA RepairDataDevelopmentDoseEventFailureFemaleGenerationsGlucoseGramicidin SHeart ArrestHistologicImageIn VitroInfantInjuryIntracranial HemorrhagesIschemiaLinkMediatingMetabolismMitochondriaMitochondrial DNAModelingMotorNADHNecrosisNerve DegenerationNeurological outcomeNuclearOrganismOutcomeOxygenPathogenesisPharmaceutical PreparationsPlacebosPoly Adenosine Diphosphate RibosePoly(ADP-ribose) Polymerase InhibitorPoly(ADP-ribose) PolymerasesPolymersQuality of lifeRandomizedRattusReactive Oxygen SpeciesRegimenReportingResearchRoleSeptic ShockShockSourceStatus EpilepticusStrokeStructure-Activity RelationshipTherapeuticTimeTraumatic Brain InjuryWestern Blottingage relatedapoptosis inducing factorcognitive testingdeprivationdruggable targetimprovedin vivoin vivo imaginginfancyinhibitorlipidomicsliquid chromatography mass spectrometrymalemetabolic ratenanomolarneonatal hypoxic-ischemic brain injuryneuroinflammationneuron lossneuronal survivalneuroprotectionnovelpostnatalpreservationpreventrelease factorsevere injurysexsuperresolution microscopysurvivorshiptargeted treatmenttooltranslational 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,
孩子一个普遍的贡献者限制生存质量是缺氧缺血性的破坏性影响,
脑病(HIE),无论是作为心脏骤停、中风或颅内出血病例的主要后果,
出血或癫痫持续状态、循环或败血性休克病例中的继发后遗症,
神经炎症或创伤性脑损伤(TBI); HIE的主要原因从婴儿期开始
心脏骤停的后果。由于迄今为止尚未发现治疗HIE的方法,
范式转换策略可能是必要的,以改善神经功能的结果为受害者的HIE。
因此,我们已经开发了一种新的治疗方法,通过保留关键的
通过选择性靶向线粒体中的聚(ADP-核糖)聚合酶(PARP)(mtPARP)来储存细胞能量,
将PARP靶向部分半短杆菌肽S(XJB)或三苯基磷(TPP)连接至PARP
临床上使用的抑制剂。由DNA损伤引发的缺血诱导的PARP过度激活消耗NAD+,
产生分支链聚(ADP-核糖)聚合物(PAR化),导致ATP消耗,能量衰竭,
以及由坏死和/或凋亡诱导因子(AIF)介导的死亡引起的细胞死亡。就像线粒体
需氧生物中ATP和NAD+的主要来源,保存线粒体能量储存
代表减轻HIE的逻辑“可用药”靶标。我们最近报道了线粒体-
靶向PARP 1抑制剂XJB-维利帕尼保护NAD+储存并防止氧-
葡萄糖剥夺(OGD)在体外以纳摩尔浓度。重要的是,XJB-维利帕尼选择性靶向
线粒体,从而不妨碍体外核DNA修复。我们提出挑衅性的试点数据
这表明XJB-维利帕尼和易于翻译的靶向大肠杆菌的化合物TPP-维利帕尼可以
在出生后第17天(PND)的大鼠心脏骤停后有效,发育年龄相当于年轻的
儿童和与大脑代谢高峰相关的时间。这种新型疗法的优势在于
通过选择性地靶向mtPARP而不使用
PARP 1-促进核DNA修复,并提供一种工具,以明确建立(或反驳)mtPARP的作用
在新生儿缺氧缺血性脑病发病机制中的作用
如果证明有效,mtPARP 1抑制剂将代表新颖、安全(就核DNA修复而言),
和可翻译的疗法,以减轻缺氧缺血性脑病,具有特殊的潜力,在高度脆弱的,发展中的大脑
代谢率达到最高点
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Hülya Bayir其他文献
Hülya Bayir的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Hülya Bayir', 18)}}的其他基金
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:
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:
相似海外基金
Developing Late Metal Catalytic Systems for Aerobic Partial Oxidation of Alkanes
开发烷烃有氧部分氧化的后金属催化系统
- 批准号:
2247667 - 财政年份:2023
- 资助金额:
$ 56.93万 - 项目类别:
Standard Grant
Targeting aerobic glycolysis via hexokinase 2 inhibition in Natural Killer T cell lymphomas
通过抑制己糖激酶 2 靶向自然杀伤 T 细胞淋巴瘤中的有氧糖酵解
- 批准号:
23K07830 - 财政年份:2023
- 资助金额:
$ 56.93万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Precision Medicine in Alzheimer’s Disease: A SMART Trial of Adaptive Exercises and Their Mechanisms of Action Using AT(N) Biomarkers to Optimize Aerobic-Fitness Responses
阿尔茨海默病的精准医学:使用 AT(N) 生物标志物优化有氧健身反应的适应性运动及其作用机制的 SMART 试验
- 批准号:
10581973 - 财政年份:2023
- 资助金额:
$ 56.93万 - 项目类别:
MIND Foods and Aerobic Training in Black Adults with HTN: An ADRD Prevention Pilot RCT (MAT)
MIND 食品和患有 HTN 的黑人成人的有氧训练:ADRD 预防试点随机对照试验 (MAT)
- 批准号:
10585366 - 财政年份:2023
- 资助金额:
$ 56.93万 - 项目类别:
Concurrent Aerobic Exercise and Cognitive Training to Prevent Alzheimer's in at-risk Older Adults
同时进行有氧运动和认知训练可预防高危老年人的阿尔茨海默病
- 批准号:
10696409 - 财政年份:2023
- 资助金额:
$ 56.93万 - 项目类别:
Investigating the physical and chemical controls on aerobic methane oxidation
研究好氧甲烷氧化的物理和化学控制
- 批准号:
2241873 - 财政年份:2023
- 资助金额:
$ 56.93万 - 项目类别:
Standard Grant
Effect of aerobic exercise-induced sleep changes on arterial stiffness associated with postprandial hyperglycemia.
有氧运动引起的睡眠变化对与餐后高血糖相关的动脉僵硬度的影响。
- 批准号:
23K10645 - 财政年份:2023
- 资助金额:
$ 56.93万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Pro-Resolving Inflammatory Mediators in Neurovascular Gains in Aerobic Training; a phase 2, double-blind, randomized placebo-controlled trial (PRIMiNG-AT2)
有氧训练中促进神经血管增益的炎症介质的消除;
- 批准号:
485524 - 财政年份:2023
- 资助金额:
$ 56.93万 - 项目类别:
Operating Grants
Regulators of Photoreceptor Aerobic Glycolysis in Retinal Health and Disease
视网膜健康和疾病中光感受器有氧糖酵解的调节因子
- 批准号:
10717825 - 财政年份:2023
- 资助金额:
$ 56.93万 - 项目类别:
The Effects of Aerobic Exercise on Cardiovascular Health in Postmenopausal Females: A Systematic Review and Meta-Analysis
有氧运动对绝经后女性心血管健康的影响:系统评价和荟萃分析
- 批准号:
480729 - 财政年份:2023
- 资助金额:
$ 56.93万 - 项目类别: