Mitochondrial Targeted Small Molecule Radiation Mitigators
Mitochondrial Targeted Small Molecule Radiation Mitigators
批准号:
8010782
负责人:
JOEL S GREENBERGER
金额:
$25.01万
依托单位国家:
美国
项目类别:
财政年份:
2010
资助国家:
美国
项目状态:
已结题
起止时间:
2010-09-01 至 2015-08-31
关键词:
AcuteAdultAdverse effectsAnimalsAntioxidantsBindingBurn injuryCarbonCarbon NanotubesDevelopmentDrug Delivery SystemsDrug FormulationsDrug KineticsEpithelialEpithelial CellsFemaleGoalsHistopathologyHourInjuryIntestinesLate EffectsLigandsLipidsLiposomesLungMarrowMethodsMitochondriaModificationMusNitric Oxide SynthaseOrganPharmaceutical PreparationsPharmacodynamicsPlasmidsProductionProteinsRadiationRegimenSafetySystemTerrorismTestingTherapeuticTimeTransgenesWhole-Body Irradiationbasebonecheminformaticsdrug structureimprovedin vivoinhibitor/antagonistirradiationmalenanoparticlenovelpregnantsmall moleculetargeted deliverytime useuptakewound
中文摘要
线粒体靶向抗氧化剂转基因产物MnSOD质粒脂质体的研究表明
是有效的电离辐射损伤保护剂和缓释剂,但体内基因产品需要数小时
制作。一种小分子线粒体靶向去氧核苷(GS)-氮氧化物,JP4-039是一种快速的
代理全身照射(TBI)损伤缓解剂,是贝塔辐射的有效局部治疗方法
C57BL/6HNsd小鼠烧伤及复合伤(照射/骨伤)的实验研究第一个具体目标是测试
线粒体靶向GS-氮氧化物增强辐射缓解的假说可以通过以下方式改善
碳纳米囊结合和内皮或上皮靶向脂质体递送。第二个具体问题
目的验证线粒体靶向小分子(GS-NOS-1、XJB-5-133和MCF-201)的假说。
89将是有效的辐射损伤缓释剂,碳纳米胶囊和脂质体也会增强
定向投放。第三个特定目的是检验小分子p53/mdm2/mdm4
抑制剂BEB55和BEB59是有效的脑损伤缓释剂,可被碳纳米胶囊和脂质体增强
瞄准目标。成年男性和女性、21日龄青春期前各药物最佳辐射缓解效果
然后,小鼠、E13只怀孕雌性小鼠及其后代将被组合在一种多药物方案中。正性
急性和晚期效应的对照药物为小环状MnSOD-质粒脂质体和双转基因MnSOD,
MT-CAT-质粒脂质体。方法包括定时释放可降解碳纳米胶囊结合小分子
分子,内皮细胞p-CAM靶向或,上皮I-CAM,靶向脂质体,器官特异性肠道,
骨髓和肺线粒体药物摄取的ESR定量,药代动力学研究,全身
辐射和器官组织病理学。一个长远的目标是发展一个实用的
局部/经皮给药,在创伤性脑损伤后24小时或更晚给予时有效。这些研究
应建立和优化新型多药线粒体靶向治疗辐射损伤
适用于辐射反恐。
英文摘要
Mitochondrial targeted antioxidant transgene product MnSOD delivered by plasmid liposomes has shown to
be an effective ionizing irradiation damage protector and mitigator but requires hours for in vivo gene product
production. A small molecule mitochondrial targeted hemlgramacidin (GS)-nitroxide, JP4-039, is a rapid
acting total body irradiation (TBI) damage mitigator, and is an effective topical therapeutic for beta irradiation
burns and combined injury (irradiation/bone wound) in C57BL/6HNsd mice. The First Specific Aim tests the
hypothesis that enhanced radiation mitigation by mitochondrial targeted GS-nitroxide can be improved by
carbon nanocapsule binding and endothelial or epithelial targeted liposome delivery. The Second Specific
Aim tests the hypothesis that mitochondrial targeted small molecules (GS-NOS-1) XJB-5-133 and MCF-201-
89 will be effective radiation damage mitigators, also enhanced by carbon nanocapsule, and liposome
targeted delivery. The Third Specific Aim tests the hypothesis that the small molecule p53/mdm2/mdm4
inhibitors, BEB55 and BEB59 are effective TBI mitigators, enhanced by carbon nanocapsule, and liposome
targeting. Optimized radiation mitigation by each drug in adult male and female, 21 day old prepubescent
mice, E13 pregnant females and their progeny will then be combined in a multidrug regimen. Positive
controls for acute and late effects will be mini circle MnSOD-plasmid liposomes, and dual transgene MnSOD,
mt-CAT-plasmid liposomes. Methods include timed-release degradable carbon nanocapsule bound small
molecules, endothelial p-CAM targeted or, epithelial i-CAM, targeted liposomes, organ specific intestinal,
marrow, and lung mitochondrial drug uptake quantitation by ESR, phamnacokinetics studies, total body
irradiation, and organ histopathology. A long term goal is the development of a practical
topical/transdermally delivered mitigator that is effective when given 24 hrs or later after TBI. These studies
should establish and optimize novel multidrug mitochondrial targeting for radiation damage mitigation
applicable for use in radiation counter terrorism.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
LR-IL-22 for Mitigation and Management of Radiation Injuries
-
批准号:10569299
-
项目类别:
-
资助金额:$56.02万
-
财政年份:2022
-
负责人:JOEL S GREENBERGER
-
依托单位:
Mitigation of Ionizing Irradiation-Induced Intestinal Damage by Second-Generation Probiotics LR-IL-22 and LR-IFN-β
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批准号:10380676
-
项目类别:
-
资助金额:$30.0万
-
财政年份:2021
-
负责人:JOEL S GREENBERGER
-
依托单位:
Pilot Project's Core
-
批准号:8010803
-
项目类别:
-
资助金额:$41.46万
-
财政年份:2010
-
负责人:JOEL S GREENBERGER
-
依托单位:
Administrative Core
-
批准号:8010802
-
项目类别:
-
资助金额:$12.46万
-
财政年份:2010
-
负责人:JOEL S GREENBERGER
-
依托单位:
Mitochondrial Targeting Against Radiation Damage
-
批准号:7922793
-
项目类别:
-
资助金额:$30.0万
-
财政年份:2009
-
负责人:JOEL S GREENBERGER
-
依托单位:
Mechanism of Irradiation Pulmonary Fibrosis
-
批准号:8082771
-
项目类别:
-
资助金额:$28.27万
-
财政年份:2008
-
负责人:JOEL S GREENBERGER
-
依托单位:
Mechanism of Irradiation Pulmonary Fibrosis
-
批准号:7364772
-
项目类别:
-
资助金额:$29.14万
-
财政年份:2008
-
负责人:JOEL S GREENBERGER
-
依托单位:
Mechanism of Irradiation Pulmonary Fibrosis
-
批准号:7645724
-
项目类别:
-
资助金额:$29.14万
-
财政年份:2008
-
负责人:JOEL S GREENBERGER
-
依托单位:
Mechanism of Irradiation Pulmonary Fibrosis
-
批准号:8270375
-
项目类别:
-
资助金额:$28.27万
-
财政年份:2008
-
负责人:JOEL S GREENBERGER
-
依托单位:
Mechanism of Irradiation Pulmonary Fibrosis
-
批准号:7849691
-
项目类别:
-
资助金额:$29.14万
-
财政年份:2008
-
负责人:JOEL S GREENBERGER
-
依托单位:
CAREER DEVELOPMENT PROGRAM
-
批准号:7088511
-
项目类别:
-
资助金额:$7.0万
-
财政年份:2006
-
负责人:JOEL S GREENBERGER
-
依托单位:
Mitochondrial Targeting Against Radiation Damage
-
批准号:7126387
-
项目类别:
-
资助金额:$201.16万
-
财政年份:2005
-
负责人:JOEL S GREENBERGER
-
依托单位:
Mitochondrial Targeting Against Radiation Damage
-
批准号:7479163
-
项目类别:
-
资助金额:$202.46万
-
财政年份:2005
-
负责人:JOEL S GREENBERGER
-
依托单位:
Mitochondrial Target for Radiation Mitigation
-
批准号:8515290
-
项目类别:
-
资助金额:$271.52万
-
财政年份:2005
-
负责人:JOEL S GREENBERGER
-
依托单位:
Mitochondrial Target for Radiation Mitigation
-
批准号:8718982
-
项目类别:
-
资助金额:$282.72万
-
财政年份:2005
-
负责人:JOEL S GREENBERGER
-
依托单位:
Administrative Core
-
批准号:8940565
-
项目类别:
-
资助金额:$9.74万
-
财政年份:2005
-
负责人:JOEL S GREENBERGER
-
依托单位:
Signature-Directed Combination Mitigator Therapy Based on GS-Nitroxides
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批准号:9127903
-
项目类别:
-
资助金额:$44.98万
-
财政年份:2005
-
负责人:JOEL S GREENBERGER
-
依托单位:
MnSOD-PL Irradiation Protection of the Oral Cavity
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批准号:6874571
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项目类别:
-
资助金额:$23.92万
-
财政年份:2005
-
负责人:JOEL S GREENBERGER
-
依托单位:
Mitochondrial Targeting Against Radiation Damage
-
批准号:7029375
-
项目类别:
-
资助金额:$200.0万
-
财政年份:2005
-
负责人:JOEL S GREENBERGER
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依托单位:
Training and Education
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批准号:7055215
-
项目类别:
-
资助金额:$12.76万
-
财政年份:2005
-
负责人:JOEL S GREENBERGER
-
依托单位:
海外基金