Mechanisms of ASIC-mediated neuronal injury
Mechanisms of ASIC-mediated neuronal injury
批准号:
10440235
负责人:
ROGER Pancoast SIMON
金额:
$31.31万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-12-15 至 2024-03-31
关键词:
ASIC channelAcidosisAcidsAcuteAmilorideAttenuatedBrain InjuriesBrain IschemiaCationsCause of DeathCell DeathCell surfaceDataFamilyFunctional disorderGlucoseGoalsInjuryIonsIschemiaIschemic Brain InjuryIschemic Neuronal InjuryIschemic StrokeLaboratoriesLeadLightMediatingMembraneMolecularMorbidity - disease rateMultiple SclerosisNatureNeurologicNeuronal InjuryNeuronsOxygenPathway interactionsPermeabilityPharmacologyPharmacotherapyPlayProteinsProtonsRIPK1 geneReportingRoleSignal PathwaySignal TransductionSignaling MoleculeSpinal cord injuryStrokeSurfaceTestingTherapeuticTherapeutic InterventionToxic effectTrace ElementsTraumatic Brain InjuryZincaxonal degenerationcell injurydeprivationdesensitizationdisabilityeffective therapyinhibitormembermortalitymutantnervous system disordernew therapeutic targetnovelnovel therapeutic interventionpublic health relevancerecruitresponseside effectstroke interventionsuccesstherapeutically effectivetrafficking
中文摘要
摘要
缺血性中风是导致死亡和长期残疾的主要原因。现行药品
治疗仅限于tPA,其具有低成功率和潜在的严重副作用。
酸中毒是神经系统疾病如脑缺血的常见特征,并且已经被
在中风中起关键作用。然而,这些机制仍然难以捉摸。的
发现质子激活一个独特的阳离子通道家族,酸敏感离子
通道(ASIC),为酸信号传导和酸中毒介导的脑损伤提供了新的线索。的
过去10年来,我们实验室的研究提供了令人信服的证据,表明
ASIC1a的激活显著促进酸中毒介导的缺血性脑损伤。
在我们的初步报告之后,其他人已经证明了ASIC1a激活在
脊髓损伤、创伤性脑损伤和轴突变性。因此,ASIC1a代表
新的治疗靶点。尽管它在神经系统疾病中的作用已经确立,但详细的
中风中ASIC1a介导的神经元损伤的潜在机制仍不清楚。我们现在
有强有力的证据表明,除了记录良好的Ca2+毒性,
增加的ASIC1a表面表达、Zn 2+毒性和离子毒性的组合
传导独立的细胞死亡通路参与ASIC介导的神经元凋亡
缺血损伤。本申请的目的是研究详细的分子
ASIC介导的神经元损伤的机制和途径。的限制条件下
目前可获得的靶向这些通道的药理学抑制剂,例如非特异性
阿米洛利和大分子性质的PcTX1,拟议的研究可能会揭示新的,
缺血性脑损伤的替代治疗策略。
英文摘要
Abstract
Ischemic stroke is a leading cause of death and long-term disability. Current drug
treatment is limited to tPA, which has a low success rate and potentially severe side effects.
Acidosis is a common feature of neurological disorders such as brain ischemia, and it has been
shown to play a critical role in stroke. The mechanisms, however, remained elusive. The
discovery that protons activate a distinct family of cation channels, the acid-sensing ion
channels (ASICs), has shed new light on acid-signaling and acidosis-mediated brain injury. The
studies in our laboratories in the past 10 years have provided convincing evidence suggesting
that activation of ASIC1a contributes markedly to acidosis-mediated ischemic brain injury.
Following our initial report, others have demonstrated an important role for ASIC1a activation in
spinal cord injury, traumatic brain injury, and axon degeneration. Thus, ASIC1a represents a
novel therapeutic target. Despite its well-established role in neurological disorders, the detailed
mechanisms underlying ASIC1a-mediated neuronal injury in stroke remain unclear. We now
have strong evidence suggesting that, besides the well-documented Ca2+ toxicity, a
combination of increased ASIC1a surface expression, Zn2+ toxicity, and an ion
conducting independent cell death pathway participate in ASIC-mediated neuronal
injury in ischemia. The objective of this application is to investigate the detailed molecular
mechanisms and pathways underlying ASIC-mediated neuronal injury. Given the limitations of
currently available pharmacological inhibitors that target these channels, e.g. the non-specificity
of amiloride and large molecule nature of PcTX1, the proposed studies may disclose novel and
alternative therapeutic strategies for ischemic brain injury.
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会议论文
Mechanisms of ASIC-mediated neuronal injury
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批准号:9820250
-
项目类别:
-
资助金额:$31.31万
-
财政年份:2017
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负责人:ROGER Pancoast SIMON
-
依托单位:
Mechanisms of ASIC-mediated neuronal injury
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批准号:10597668
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资助金额:$31.31万
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国内基金
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