LPA Receptor Modulators as Radioprotectants
LPA 受体调节剂作为辐射防护剂
基本信息
- 批准号:7326663
- 负责人:
- 金额:$ 9.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-08-01 至 2008-01-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdverse effectsAgonistAlkenesAnimalsApoptoticAstronautsBiological AssayBioterrorismCancer PatientCancer SurvivorCessation of lifeChemotherapy-Oncologic ProcedureClassDNA FragmentationDataDoseEdg4 ProteinEpithelial CellsEventExplosionExposure toFaceFoundationsG-Protein-Coupled ReceptorsGoalsGrowth FactorHeadHematopoieticHourHumanHydrocarbonsIn VitroIndustryIntestinesIonizing radiationKnockout MiceLeadLengthLifeLigandsLipidsLysophosphatidic Acid ReceptorsLysophospholipidsMedicalMilitary PersonnelModalityModificationMolecularMolecular TargetMucositisMusMuscle RigidityNatureNuclearNuclear AccidentsObject AttachmentPeroxisome ProliferationPeroxisome Proliferator-Activated ReceptorsPhasePhospholipidsPopulationPositioning AttributeQuality of lifeRadiationRadiation InjuriesRadiation therapyRadiation-Protective AgentsRadioprotectionRelative (related person)RiskScreening procedureStem cellsStructure-Activity RelationshipSulfhydryl CompoundsSyndromeTechnologyTerrorismTestingTherapeuticTherapeutic AgentsWorkanalogattenuationbasecell typedesigndirty bombgastrointestinalhuman GPR4 proteinimprovedinorganic phosphateintraperitonealirradiationlysophosphatidic acidmicrobialnovelphosphonatepreventradiation effectreceptorresearch and developmentresearch studyscaffoldsmall moleculestereochemistrysubcutaneoussuccessthiophosphatetranscription factor
项目摘要
DESCRIPTION (provided by applicant): The goal of this Phase I proposal is to perform lead optimization of a novel small molecular radioprotectant based on the Rx100 scaffold. Rx100, a metabolically stabilized analog of phospholipid growth factor lysophosphatidic acid (LPA), has shown promising results in mice, protecting the gut from radiation-induced mucositis, and preventing death when administered either before or up to six hours after exposure to ionizing radiation. Our knockout mouse studies indicate that LPA2 is the molecular target for radioprotection. Rx100 is a potent and full agonist at LPA2 GPCR; however, it is a partial agonist of the pro-apoptotic lipid-regulated transcription factor PPAR?. Based on our preliminary findings, we hypothesize that (1) synthetic optimization of Rx100 will provide selective LPA2 agonists devoid of PPAR? activity; (2) Rx100 analogs could be developed as potent radioprotective agents for ameliorating the gastrointestinal mucositis accompanied by cancer radiotherapy, leading to enhancement of the efficacy of radiotherapy and improvement of cancer survivors' quality of life; and (3) Rx100 analogs could be developed as a medical countermeasure against acute gastrointestinal syndrome and hematopoietic syndrome caused by unintended whole-body exposure to radiation in the events of nuclear accident or radiation terrorism. Studies proposed herein are designed to test the hypothesis that the activity of Rx100 analogs can be optimized, and the success of these studies would provide a strong foundation for the hypothesis that this new class of therapeutic agents can be developed for the effective protection of human life from inadvertent radiation exposure. The product(s) have marketable potential, because they could be used for the protection of populations potentially subjected to accidental, military, or therapeutic radiation exposure, workers in nuclear industry, astronauts and cancer patients. Unintended exposure to radiation via a nuclear accident, explosion of a "dirty bomb," can have devastating consequences to mankind. Radiation terrorism - a form of bioterrorism that exposes humans to damaging levels of radiation - is a real threat our nation faces everyday with no lesser risks than other modalities of microbial bioterrorism. Death from radiation treatment occurs from either gastrointestinal syndrome or hematopoietic syndrome due to the extreme sensitivity of stem cells to ionizing radiation. RxBio proposes to develop therapeutic agents based on Rx100's lead scaffold to prevent or minimize the damage due to radiation exposure and save innocent life in case of a nuclear or dirty-bomb explosion. This technology also offers applications for the attenuation of the side effects of radiation and chemotherapy of cancer.
描述(由申请人提供):本I期提案的目标是对基于Rx100支架的新型小分子辐射防护剂进行先导优化。Rx100是磷脂生长因子溶血磷脂酸(LPA)的代谢稳定类似物,在小鼠中显示出有希望的结果,保护肠道免受辐射诱导的粘膜炎,并在暴露于电离辐射之前或之后长达6小时内给药时防止死亡。我们的敲除小鼠研究表明,LPA 2是辐射防护的分子靶点。Rx100是LPA 2 GPCR的有效和完全激动剂;然而,它是促凋亡脂质调节转录因子PPAR?的部分激动剂。基于我们的初步研究结果,我们假设:(1)Rx100的合成优化将提供选择性LPA 2激动剂缺乏过氧化物酶体增殖物激活受体?活动;(2)Rx100类似物可作为一种有效的放射防护剂,用于改善肿瘤放疗引起的胃肠道黏膜炎,从而提高放疗疗效,改善肿瘤生存者的生活质量;(3)Rx100类似物可开发为治疗非预期的全-在核事故或辐射恐怖事件中的身体辐射暴露。本文提出的研究旨在测试Rx100类似物的活性可以被优化的假设,这些研究的成功将为这类新的治疗剂可以被开发用于有效保护人类生命免受意外辐射暴露的假设提供坚实的基础。这些产品具有销售潜力,因为它们可用于保护可能遭受意外、军事或治疗性辐射照射的人群、核工业工人、宇航员和癌症患者。通过核事故、“脏弹”爆炸意外暴露于辐射,可能对人类造成毁灭性后果。辐射恐怖主义--一种使人类暴露在破坏性辐射水平下的生物恐怖主义--是我们国家每天面临的真实的威胁,其风险不亚于其他形式的微生物生物恐怖主义。由于干细胞对电离辐射的极端敏感性,放射治疗的死亡发生于胃肠道综合征或造血综合征。RxBio建议开发基于Rx100的铅支架的治疗剂,以防止或最大限度地减少辐射暴露造成的损害,并在核爆炸或脏弹爆炸时挽救无辜生命。该技术还提供了用于减轻癌症放疗和化疗的副作用的应用。
项目成果
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