Chromium Mesoporphyrin in the Prevention of Neonatal Jaundice
铬中卟啉预防新生儿黄疸
基本信息
- 批准号:7945355
- 负责人:
- 金额:$ 36.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-30 至 2012-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectBilirubinBiologicalBiological AssayCell DeathCessation of lifeClinicalClinical ResearchDiseaseEnzymesErythemaEvaluationExcretory functionExtremely Low Birth Weight InfantFailureFree RadicalsFutureGenetic TranscriptionHemeHumanHyperbilirubinemiaIcterusIn VitroInfantKernicterusKidneyLaboratoriesLightLipid PeroxidationLipidsLiverLong-Term EffectsMembraneMessenger RNAMetabolicMetalloporphyrinsMiningModelingMonitorMonkeysMusNeonatalNeonatal JaundiceNeurodevelopmental ImpairmentNewborn AnimalsNewborn InfantOperative Surgical ProceduresOralOral AdministrationOxygenasesPatternPharmaceutical PreparationsPhase III Clinical TrialsPhotosensitivityPhotosensitizationPhotosensitizing AgentsPhototherapyPhototoxicityPreventionPrevention approachProductionProteinsRandomizedRattusRegulationRh IsoimmunizationRiskSafetySinglet OxygenSkinSpleenStressTherapeuticTherapeutic AgentsTissuesWarWorkabsorptionalternative treatmentanalogbasebrain tissuechromium mesoporphyrincytotoxicitydesigndirect applicationenzyme activityheme aheme oxygenase-1heme oxygenase-2in vivoinhibitor/antagonistmortalitymouse modelneonatenonhuman primatepre-clinicalpublic health relevanceresponsetherapeutic targettin mesoporphyrintreatment strategy
项目摘要
DESCRIPTION (provided by applicant): Neonatal jaundice occurs in 60-70% of all newborn infants. It is caused not only by an overproduction of bilirubin, but also by a transient failure to excrete this metabolite. Hyperbilirubinemia is exacerbated by hemolytic diseases, such as Rhesus isoimmunization and ABO incompatibility, which result in increased bilirubin production, as well as diseases that result in decreased bilirubin excretion. The rate-limiting enzyme in the production of bilirubin is heme oxygenase (HO), and as such is a key therapeutic target. Inhibition of HO activity has been shown to protect newborns from excessive hyperbilirubinemia. Heme analogs, metalloporphyrins (Mps), are potent competitive inhibitors of HO enzyme activity. The use of Mps as oral therapeutic agents may be an effective approach for the prevention and treatment of hyperbilirubinemia. In this proposal, we will extend our preliminary studies of chromium mesoporphyrin (CrMP), which is a potent HO inhibitor, absorbable orally and photo-inert, in the newborn mouse. In anticipation of positive findings, we propose to extend these studies further to the non-human primate newborn model. In our laboratory, we have continued to develop and validate assays to monitor in vivo heme degradation and HO-1 transcriptional patterns and in vitro enzymatic activity of HO so that we can evaluate regulation and expression at these two levels. Application of these approaches to the neonatal mouse model is a natural extension of our work with the newborn rat, mouse, and monkey models. The results of this project will assist in the design of future clinical studies of CrMP by providing both spatial and temporal information pertaining to its direct effects on the enzymatic target, its expression, and subsequent short- and long-term effects on the newborn animal. The specific aims of this application are directed at evaluating the efficacy and safety of CrMP for the treatment of neonatal jaundice through inhibition of HO activity and serves as a basis for a "pre-clinical" IND evaluation of its potential efficacy and safety for use in the human neonate, with particular emphasis on short- and long-term effects in the heme-loaded newborn mouse. Use of a newborn mouse model should permit well-controlled systematic studies preceding the administration of CrMP, a very promising inhibitor, for the treatment of neonatal jaundice.
PUBLIC HEALTH RELEVANCE: Heme oxygenase (HO) is a key therapeutic target in the prevention of neonatal jaundice. We have been investigating the efficacy and safety of metalloporphyrins (Mps) for their potential use in the treatment of neonatal jaundice. In this proposal, we propose to extend our studies of CrMP in the mouse because CrMP is a potent HO inhibitor, absorbable orally and photo-inert. The specific aims of this application serve as a basis for a "pre-clinical" IND evaluation of potential efficacy and safety of CrMP for use in the human neonate, with particular emphasis on short- and long-term effects in the heme-loaded newborn mouse.
描述(由申请人提供):新生儿黄疸发生在所有新生儿的60-70%。它不仅是由胆红素的过度产生引起的,而且也是由这种代谢产物的短暂排泄失败引起的。高胆红素血症会因溶血性疾病而加重,如导致胆红素产生增加的恒河猴同种免疫和ABO不相容性,以及导致胆红素排泄减少的疾病。胆红素产生的限速酶是血红素加氧酶(HO),因此是关键的治疗靶点。HO活性的抑制已被证明可以保护新生儿免于过度高胆红素血症。血红素类似物,金属卟啉(Mps),是HO酶活性的有效竞争性抑制剂。使用Mps作为口服治疗剂可能是预防和治疗高胆红素血症的有效途径。在这个建议中,我们将扩大我们的初步研究铬中卟啉(CrMP),这是一个有效的HO抑制剂,口服吸收和光惰性,在新生小鼠。在积极的研究结果的预期,我们建议将这些研究进一步扩展到非人灵长类新生儿模型。在我们的实验室中,我们继续开发和验证检测方法,以监测体内血红素降解和HO-1的转录模式和体外HO酶活性,以便我们可以评估这两个水平的调控和表达。将这些方法应用于新生小鼠模型是我们对新生大鼠、小鼠和猴模型工作的自然延伸。该项目的结果将有助于设计未来的临床研究的CrMP通过提供空间和时间信息有关的酶的目标,其表达,以及随后的短期和长期的影响对新生动物的直接影响。本申请的具体目的是评价CrMP通过抑制HO活性治疗新生儿黄疸的有效性和安全性,并作为其用于人类新生儿的潜在有效性和安全性的“临床前”IND评价的基础,特别强调在血红素负载的新生小鼠中的短期和长期作用。新生小鼠模型的使用应允许良好的控制系统的研究之前,管理的CrMP,一个非常有前途的抑制剂,用于治疗新生儿黄疸。
公共卫生相关性:血红素加氧酶(HO)是预防新生儿黄疸的关键治疗靶点。我们一直在研究金属卟啉(Mps)在新生儿黄疸治疗中的有效性和安全性。在这个提议中,我们建议扩展我们在小鼠中的CrMP研究,因为CrMP是一种有效的HO抑制剂,可口服吸收且具有光惰性。本申请的具体目的是作为CrMP用于人类新生儿的潜在有效性和安全性的“临床前”IND评价的基础,特别强调在血红素负载的新生小鼠中的短期和长期作用。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Effect of light exposure on metalloporphyrin-treated newborn mice.
光暴露对金属卟啉治疗的新生小鼠的影响。
- DOI:10.1038/pr.2012.62
- 发表时间:2012
- 期刊:
- 影响因子:3.6
- 作者:Schulz,Stephanie;Wong,RonaldJ;Kalish,FloraS;Zhao,Hui;Jang,KyuYun;Vreman,HendrikJ;Stevenson,DavidK
- 通讯作者:Stevenson,DavidK
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DAVID K STEVENSON其他文献
DAVID K STEVENSON的其他文献
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{{ truncateString('DAVID K STEVENSON', 18)}}的其他基金
Chromium Mesoporphyrin in the Prevention of Neonatal Jaundice
铬中卟啉预防新生儿黄疸
- 批准号:
7778390 - 财政年份:2009
- 资助金额:
$ 36.25万 - 项目类别:
Therapeutic Use of Heme Analogs: Absorption in Intestine
血红素类似物的治疗用途:肠道吸收
- 批准号:
7815755 - 财政年份:2009
- 资助金额:
$ 36.25万 - 项目类别:
Effects of Statins on Heme Oxygenase-1 Regulation
他汀类药物对血红素加氧酶 1 调节的影响
- 批准号:
7210136 - 财政年份:2007
- 资助金额:
$ 36.25万 - 项目类别:
SURFACTANT POSITIVE AIRWAY PRESSURE AND PULSE OXIMETRY TRIAL IN ELBW INFANTS
ELBW 婴儿的表面活性剂气道正压和脉搏血氧饱和度试验
- 批准号:
7605226 - 财政年份:2007
- 资助金额:
$ 36.25万 - 项目类别:
SURFACTANT POSITIVE AIRWAY PRESSURE AND PULSE OXIMETRY TRIAL IN ELBW INFANTS
ELBW 婴儿的表面活性剂气道正压和脉搏血氧饱和度试验
- 批准号:
7717880 - 财政年份:2007
- 资助金额:
$ 36.25万 - 项目类别:
Effects of Statins on Heme Oxygenase-1 Regulation
他汀类药物对血红素加氧酶 1 调节的影响
- 批准号:
7359601 - 财政年份:2007
- 资助金额:
$ 36.25万 - 项目类别:
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