Inter-alpha Inhibitors in Hypoxic-Ischemic Brain Injury
Inter-alpha Inhibitors in Hypoxic-Ischemic Brain Injury
批准号:
10761207
负责人:
YOW-PIN LIM
金额:
$277.69万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2014
资助国家:
美国
项目状态:
未结题
起止时间:
2014-07-01 至 2026-08-31
关键词:
AdultAffectAftercareAnimalsAnti-Inflammatory AgentsAttenuatedBindingBinding ProteinsBloodBlood gasBlood specimenBrainBrain Hypoxia-IschemiaBrain InjuriesCellsCerebral Ischemia-HypoxiaCerebral PalsyChildChromatographyClinicalClinical ResearchClinical TrialsComplementComplement ActivationDataDoseExposure toFDA approvedFamilyFutureGlycoproteinsGoalsHMGB1 geneHealthHistonesHumanHypoxic-Ischemic Brain InjuryImageInfantInflammationInflammation MediatorsInflammatoryInflammatory ResponseIschemiaLongitudinal StudiesMagnetic Resonance ImagingMatrix MetalloproteinasesMental RetardationModelingMotorNeonatalNeurologicNeuroprotective AgentsNewborn AnimalsNewborn InfantNuclear ProteinsPathway interactionsPerinatal Brain InjuryPhasePlasmaPlayPremature InfantPreventionProcessProductionPropertyProteinsPublic HealthRattusRecoveryReperfusion TherapyReplacement TherapyResolutionRestRoleSerine ProteaseSmall Business Innovation Research GrantSocietiesTherapeuticTherapeutic AgentsToxicologybehavior testbehavioral outcomebrain volumecognitive functioncytokinedesigndisabilitydrug developmentefficacy testingextracellularhigh risk infantimmunoregulationimprovedinflammatory markerinjuredinter-alpha-inhibitornatural hypothermianeonatal hypoxic-ischemic brain injuryneonateneuroprotectionneutrophilnovelpharmacodynamic biomarkerpharmacologicpotential biomarkerpre-clinicalpreclinical studypredictive markerpreterm newbornpreventprotein complexsafety testingsexstandard of caretherapeutically effectivetissue repairtreatment effecttreatment optimizationtreatment strategyyoung adult
中文摘要
围产期脑损伤导致的智力迟钝和脑瘫是最严重的残疾
英文摘要
Perinatal brain injury resulting in mental retardation and cerebral palsy is the most severe disability in
children and affects 40-148 in preterm and 1–2/1000 in full term infants. This places a huge burden on society,
emphasizing the critical need for improved prevention/treatment strategies to decrease perinatal brain injury.
Hypothermia (HT) is the only FDA approved therapy to attenuate brain damage in infants. This therapy is only
partially protective, has a narrow therapeutic window, can only be used to treat hypoxic-ischemic
encephalopathy (HIE) in full term infants, and is not approved for use in preterm infants. Therefore, additional
adjunctive therapies are urgently needed. Inter-alpha Inhibitor Proteins (IAIPs) are naturally derived
glycoproteins that have been demonstrated to play an important role in modulating host inflammatory
responses by targeting multiple, diverse inflammatory pathways. IAIPs down-regulate cytokines, inhibit serine
proteases, block complement activation, maintain neutrophils in a resting state, reduce ROS production, and bind
nuclear proteins that are released from dying cells. Our encouraging results from the recently completed SBIR
Phase II project showed that IAIPs markedly attenuate brain volume loss under normothermic conditions in
experimental neonatal HI brain injury, and that treatment with IAIPs offered equivalent neuroprotective efficacy
to HT in neonatal rats. The results of MRI imaging correlated very well with the brain volume loss in the injured
rat brains when they became young adults, facilitating efficient and long-term study of treatment effects. We
treated the rats with IAIPs immediately after the exposure to HI followed by HT. In this proposal, we will modify
our previous study paradigm to enhance IAIPs effect by providing longer sequential repeated doses after
exposure to HT. This strategy specifically targets the prolonged secondary inflammatory phase that last for
days to weeks after HI brain injury. The goal of this project is to advance the drug development process by
confirming and further developing effective therapeutic strategies using IAIPs as an alternative or adjunctive
to HT to prevent and/or attenuate HI-related brain damage in neonates. We will also explore blood IAIP levels
and other inflammatory markers as potential biomarkers to assist in future human trials. The specific aims are:
1) To optimize the treatment strategy with IAIPs in treating moderate and severe HI alone and/or after
treatment with HT: We hypothesize that multiple repeated IAIP doses after HT augments the beneficial effects
of HT by reducing the secondary inflammatory phase and improves long term histopathological and behavioral
outcomes; 2) To identify pharmacodynamic biomarkers to use in animal toxicology and clinical studies: We
hypothesize that the levels of IAIPs and the associated target proteins (HMGB1 and extracellular histones) are
altered in infants with HIE and could serve as useful predictive biomarkers in addition to Apgar/Sarnat scores,
aEEG and blood gas values to guide clinical therapy in infants. The proposed translational project is designed
to obtain robust key preclinical data in support of future early human safety and efficacy testing.
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DOI:
10.3390/ijms232113473
发表时间:
2022-11-03
期刊:
International journal of molecular sciences
影响因子:
5.6
作者:
[]
通讯作者:
DOI:
10.3390/ijms221910751
发表时间:
2021-10-04
期刊:
International journal of molecular sciences
影响因子:
5.6
作者:
[Hatayama K, Kim B, Chen X, Lim YP, Davidson JO, Bennet L, Gunn AJ, Stonestreet BS]
通讯作者:
Stonestreet BS
Time Course of Changes in the Neurovascular Unit after Hypoxic-Ischemic Injury in Neonatal Rats.
新生大鼠缺氧 - 缺血性损伤后神经血管单元的变化时间。
DOI:
10.3390/ijms23084180
发表时间:
2022-04-10
期刊:
International journal of molecular sciences
影响因子:
5.6
作者:
[]
通讯作者:
DOI:
10.2174/1381612826666200421123242
发表时间:
2020
期刊:
Current pharmaceutical design
影响因子:
3.1
作者:
[Chen X, Song D, Nakada S, Qiu J, Iwamoto K, Chen RH, Lim YP, Jusko WJ, Stonestreet BS]
通讯作者:
Stonestreet BS
DOI:
10.1016/j.expneurol.2020.113442
发表时间:
2020-12
期刊:
Experimental neurology
影响因子:
5.3
作者:
[Schuffels S, Nakada S, Wu Y, Lim YP, Chen X, Stonestreet BS]
通讯作者:
Stonestreet BS
共 6 条
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Rapid detection of neonatal sepsis
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Bioprocessing of Plasma Therapeutic Proteins using Sequential Affinity Monolithic
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财政年份:2007
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依托单位:
Inter-alpha Inhibitors in Detecting CNS Cancer
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批准号:6837867
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资助金额:$13.99万
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财政年份:2005
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负责人:YOW-PIN LIM
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依托单位:
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批准号:6913712
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项目类别:
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资助金额:$18.5万
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财政年份:2004
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依托单位:
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批准号:6814783
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项目类别:
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资助金额:$21.32万
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财政年份:2004
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负责人:YOW-PIN LIM
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依托单位:
Predictive value of inter-alpha inhibitors in sepsis
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批准号:6645521
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项目类别:
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资助金额:$13.12万
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财政年份:2003
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负责人:YOW-PIN LIM
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依托单位:
THERAPEUTIC USE OF INTER-ALPHA INHIBITOR IN SEPSIS
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批准号:6790170
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项目类别:
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资助金额:$51.75万
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财政年份:2002
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负责人:YOW-PIN LIM
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依托单位:
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批准号:6486378
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财政年份:2002
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负责人:YOW-PIN LIM
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依托单位:
THERAPEUTIC USE OF INTER-ALPHA INHIBITOR IN SEPSIS
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批准号:6906476
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项目类别:
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资助金额:$98.39万
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负责人:YOW-PIN LIM
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依托单位:
海外基金