Rusalatide Acetate (TP508) Mitigation of Genotoxic Radiation Damage in Human Lens Epithelial Cells
醋酸鲁沙拉肽 (TP508) 减轻人晶状体上皮细胞的基因毒性辐射损伤
基本信息
- 批准号:10384634
- 负责人:
- 金额:$ 32.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcetatesAmyloid beta-ProteinAnimal ModelAnimalsApoptosisBCL2 geneBiological AssayBlindnessCASP3 geneCHEK1 geneCHEK2 geneCancer PatientCataractCell CycleCell Cycle RegulationCell DeathCell LineCell ProliferationCell SurvivalCellsComplexCorneaCrystallinsCyclinsDNA Double Strand BreakDNA RepairDNA-PKcsDataDiseaseDoseDouble Strand Break RepairDrug Delivery SystemsEndothelial CellsEpithelialEpithelial CellsEventFamilyFunctional disorderFutureGenesHealthHourHumanIndividualInvestigationLaboratoriesLeadLens FiberLifeMedical EconomicsMethodsMitoticMolecularNecrosisOccupational ExposureOral mucous membrane structurePathway interactionsPeptidesPersonsPharmaceutical PreparationsPhasePopulationProceduresProteinsProton RadiationRadiationRadiation Dose UnitRadiation Induced DNA DamageRadiation ProtectionRadiation ToleranceRadiation exposureRadiation induced damageRadiation therapyRadioRetinaRetinal DiseasesRiskRoentgen RaysScheduleSignal PathwaySignal Transduction PathwaySignaling ProteinSocial ImpactsSocietiesStainsTP53 geneTechniquesTestingTherapeuticTimeTissuesTreatment ProtocolsWestern BlottingXerostomiadosageeconomic impacteye drynessfiber cellgenotoxicityhealth related quality of lifeimproved outcomeirradiationlensoptimal treatmentsp53-binding protein 1preventpromoterprotective effectprotein aggregationprotein expressionradiation adverse effectregenerativeresponsesenescenceside effectsingle fraction radiation
项目摘要
Cancer patients benefit from radiation therapy but can incur side effects to non-targeted tissues including
cataracts. Although not directly life threatening, cataract disease has major medical, economic, and social
impacts on individuals, families, and society as a whole. Radiation-induced lens opacification is a complex
event and has been attributed to DNA double strand breaks (DSB) in the germinative epithelium, leading to
defective differentiation of lens fiber cells and subsequent abnormal folding of lens proteins. Rusalatide
acetate (TP508) is a radio-modulating peptide that has been shown to increase survival of irradiated
animals via activation of signal transduction pathways in endothelial cells, initiating repair of DSB, increasing
NO levels and reversing of endothelial cell dysfunction. This investigation will determine if, in the absence of
endothelial cells, TP508 will have a similar effect on human lens epithelial cells (HLEC) and mitigate
radiation induced pathophysiological pathways that lead to DSB. The hypothesis is that through the direct
activation of molecular pathways in irradiated HLEC, TP508 treatment will mitigate or repair DSB. In
contrast to other investigative approaches that focus on a single downstream mechanism, this investigation
will examine molecular activity of TP508 across multiple pathophysiological pathways associated with the
health of HLEC. Study aims are to establish the molecular activity and optimum dosage thresholds, and
timing of treatments of TP508 in mitigating X-ray or proton radiation damage with single fraction exposures
of 0.5, 1.0, 2.0, or 4 Gy in HLEC (CRL-11421 [B3] and SRA01/04 lines). Aim (1) is to determine the most
optimized concentration and administration schedule for TP508 effects on radiation induced HLEC viability
using a clonogenic survival assay, MTT assay, and cell doubling time to assess the effects of various
concentrations of TP508 on the sensitivity of HLECs applied before and after irradiation. Aim (2) is to
further identify the effects of TP508 on specific HLEC molecular responses, using the most optimized
concentration and administration schedule of TP508 comparing the single fraction radiation exposures
applied with or without TP508, and analyzed with assays for apoptosis, necrosis, senescence, mitotic
catastrophe and protein expression; 53BP1 foci staining for dynamics of DSB; and western blot assays for
related signaling pathways and protein profiles including amyloid beta, an early marker of cataract
formation. Studies are expected to provide the following: (i) determine if TP508 provides a survival effect on
irradiated HLEC at different doses applied before and after radiation; (ii) identify if the molecular
mechanisms and protein profiles underlying the protective effect of TP508 in HLEC at different doses of
radiation are attributed to DSB repair; and (iii) determine the most effective dosage and timing (before or
after radiation) of TP508 application. Successfully developed, future investigations of TP508 could expand
its application to mitigate additional radiation side effects including dry eye, retinopathy, and xerostomia.
.
癌症患者受益于放射治疗,但可能对非靶组织产生副作用,包括
白内障白内障疾病虽然不直接威胁生命,但在医疗、经济和社会方面具有重大意义
对个人、家庭和整个社会的影响。辐射诱导的透镜混浊是一种复杂的
事件,并已被归因于DNA双链断裂(DSB)在生发上皮,导致
透镜纤维细胞的分化缺陷和随后的透镜蛋白质的异常折叠。鲁萨尔茨基
乙酸酯(TP 508)是一种放射性调节肽,已被证明可以增加受辐射的
动物通过激活内皮细胞中的信号转导途径,启动DSB的修复,增加
NO水平和逆转内皮细胞功能障碍。这项调查将确定,如果没有
因此,TP 508对人透镜上皮细胞(HLEC)具有类似的作用,并且减轻了对人晶状体上皮细胞(HLEC)的刺激。
辐射诱导的病理生理途径导致DSB。假设是,通过直接
激活照射后HLEC中的分子通路,TP 508治疗将减轻或修复DSB。在
与关注单一下游机制的其他调查方法相比,
将检查TP 508在与糖尿病相关的多种病理生理学途径中的分子活性。
HLEC的健康研究目的是确定分子活性和最佳剂量阈值,
TP 508治疗减轻X射线或质子辐射损伤的时间选择
HLEC中的剂量为0.5、1.0、2.0或4戈伊(CRL-11421 [B3]和SRA 01/04系)。目的(1)是确定最
TP 508对辐射诱导的HLEC活力影响的优化浓度和给药方案
使用克隆形成存活测定、MTT测定和细胞倍增时间来评估各种
TP 508浓度对照射前后应用的HLEC的敏感性的影响。目标(2)是
进一步确定TP 508对特异性HLEC分子反应的影响,使用最优化的
TP 508的浓度和给药方案,比较单次辐射暴露
在有或没有TP 508的情况下施用,并用细胞凋亡、坏死、衰老、有丝分裂
突变和蛋白质表达; 53 BP 1焦点染色用于DSB的动力学;和蛋白质印迹测定用于DSB的免疫印迹分析。
相关的信号通路和蛋白质谱,包括淀粉样蛋白β,白内障的早期标志物
阵研究预期提供以下内容:(i)确定TP 508是否提供了对受试者的存活效果。
在辐射之前和之后施加不同剂量的经辐射的HLEC;(ii)确定分子是否
TP 508在不同剂量下对HLEC的保护作用的机制和蛋白质谱
辐射归因于DSB修复;以及(iii)确定最有效的剂量和时间(之前或之后)。
辐射后)的TP 508应用。成功开发,TP 508的未来研究可以扩大
其用于减轻包括干眼症、视网膜病和口干症的额外辐射副作用。
.
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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USHA P ANDLEY其他文献
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{{ truncateString('USHA P ANDLEY', 18)}}的其他基金
Rusalatide Acetate (TP508) Mitigation Effect on Radiation Induced Keratopathy
醋酸鲁沙来肽 (TP508) 对放射诱发的角膜病变的缓解作用
- 批准号:
10605739 - 财政年份:2023
- 资助金额:
$ 32.75万 - 项目类别:
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