Acute radiation injury alters microRNA profiles that predict late tissue-specific damage
急性辐射损伤改变了预测晚期组织特异性损伤的 microRNA 谱
基本信息
- 批准号:10088403
- 负责人:
- 金额:$ 66.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-02-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAddressAgeAnimal ModelAnimalsAttentionAutopsyBiological AssayBiological MarkersBloodBody WeightBone MarrowCaringCessation of lifeCharacteristicsChemicalsChronicComplexCox Proportional Hazards ModelsDataDependenceDevelopmentDiagnosisDiseaseDoseDose-RateEchocardiographyEventExposure toFibrosisFrightGenderGoalsHeartHematopoieticHigh-LET RadiationHistologyHomeostasisHumanImmuneImmune System DiseasesImmune systemImmunologyInbred C3H MiceIncidenceIndividualInflammationInflammatoryInfrastructureInvestigationIonizing radiationKidneyKnowledgeLate EffectsLeadLiverLongevityLungMeasurableMedicalMicroRNAsMindModelingMonitorMorbidity - disease rateMusMyeloid CellsNatureNeutronsNormal tissue morphologyNuclearOrganOutcomePancreasPancreatic enzymePathway interactionsPatientsPatternPersonsPlasmaPopulationPrognosisQuantitative Reverse Transcriptase PCRRadiationRadiation AccidentsRadiation Dose UnitRadiation InjuriesRadiation PhysicsRadiation ToxicityRadiation exposureRadiation induced damageRadiobiologyRadiometryResearchRiskRoentgen RaysScreening procedureSignal TransductionStatistical Data InterpretationSurvivorsSystemTerrorismTimeTissuesToxic effectTriageVeterinary MedicineWhole-Body IrradiationWorkX-Ray Computed Tomographybasebiodosimeterbiological adaptation to stressbiomarker panelcancer radiation therapycandidate markercirculating microRNAclinical examinationdata miningexperienceheart damageimprovedin vivoirradiationlung injurymalemiRNA expression profilingmindfulnessmortalitynonhuman primatenovelprematureradiation effectradiation-induced tissue damageresponsestatistics
项目摘要
PROJECT SUMMARY
Despite extensive investigations into the effects of radiation on normal tissues, there is currently no easy way
to quickly determine if a person has been exposed to radiation, to what dose and type, and if they are likely to
suffer serious acute or delayed consequences. Time may also be of the essence for triaging large numbers of
individuals and with that in mind have developed a robust infrastructure for the discovery and development of a
novel biodosimeter that offers a compelling solution; namely circulating microRNA (miRNA) profiling. It is
based on our extensive experience in studying survivors of acute radiation syndromes (ARS) in murine and
non-human primate models, and our understanding of the road toward the development of delayed effects,
which don’t follow the same strict time-dose constraints as ARS. Instead, they display common patterns of
inflammation and aberrant immune engagement, leading to late tissue toxicity and premature death. Our
hypothesis is that radiation-induced systemic myeloid cell mobilization and immunohematopoietic imbalance
drive late radiation damage that, remarkably, occurs only in some mice and not in others. We have compelling
evidence that dynamic events at the irradiated tissue-immune interface are reflected in a measurable shift in
the circulating miRNAs landscape suggesting that they 1) go hand-in-hand with the initial radiation insult and 2)
precede late tissue-specific radiation-induced toxicities such as fibrosis in heart and lung.
Against this backdrop we propose to develop a panel of miRNAs and build a comprehensive biomarker
platform that integrates signals from both acute and late radiation damage. Our goal is to extend our existing
knowledge from low LET exposures and determine if known patterns of miRNA changes are inherently
different for radiation of different qualities, and if the nature of the associated tissue damage also changes. In
Aim 1 we will determine broad parameters such as dose-rate and time that define radiation-induced tissue
damage in the aftermath of hematopoietic ARS caused by X-rays versus neutron exposures. We will rely on
proven, robust endpoints such clinical examination, blood work and necropsy amongst other, more tissue
specific readouts to capture multi-organ disease. Longitudinal plasma miRNA profiles will be generated for
each mouse as part of Aim 2 and aligned within the context of tissue damage to identify putative biomarker
candidates to achieve our ultimate goal and build a biomarker panel for tissue- and radiation-specific damage
(Aim 3). The study has broad relevance to acute and chronic radiation effects and it epitomizes the complex
interaction between radiation-damaged tissues and immune homeostasis. We are mindful of the challenges
that arise when comparing X-rays with neutrons using in vivo irradiation and the complexities that are inherent
in studying late morbidities. We therefore assembled a team that combines expertise in radiation biology,
immunology, miRNA profiling, radiation physics and dosimetry, veterinary care and statistics to cover all
aspects of this research.
项目摘要
尽管对辐射对正常组织的影响进行了广泛的调查,但目前还没有简单的方法
快速确定一个人是否暴露在辐射中,辐射的剂量和类型,以及他们是否可能
造成严重的急性或延迟后果。时间也可能是对大量的
个人,并铭记这一点,已经开发了一个强大的基础设施,用于发现和开发一个
新型生物剂量计提供了一个令人信服的解决方案;即循环microRNA(miRNA)谱。是
基于我们在研究小鼠急性放射综合征(ARS)幸存者方面的丰富经验,
非人类灵长类动物模型,以及我们对延迟效应发展之路的理解,
它不像ARS那样遵循严格的时间-剂量限制。相反,它们显示出
炎症和异常免疫参与,导致晚期组织毒性和过早死亡。我们
假设辐射诱导系统性骨髓细胞动员和免疫造血失衡
很明显,这种辐射损伤只发生在一些小鼠身上,而在另一些小鼠身上则没有。我们有令人信服
有证据表明,辐照组织-免疫界面处的动态事件反映在以下可测量的变化中:
循环中的miRNAs景观表明它们1)与初始辐射损伤密切相关,2)
在晚期组织特异性辐射诱导的毒性,如心脏和肺纤维化之前。
在此背景下,我们建议开发一组miRNAs,并建立一个全面的生物标志物
该平台整合了急性和晚期辐射损伤的信号。我们的目标是扩大我们现有的
低LET暴露的知识,并确定已知的miRNA变化模式是否固有地
对于不同质量的辐射,以及如果相关组织损伤的性质也改变,则不同。在
目标1我们将确定广泛的参数,如剂量率和时间,确定辐射诱导组织
X射线与中子照射引起的造血ARS后的损伤。我们将依靠
经过验证的可靠终点,如临床检查、血液检查和尸检,以及其他更多组织检查
特定读数以捕获多器官疾病。将生成纵向血浆miRNA谱,
每只小鼠作为目标2的一部分,并在组织损伤的背景下进行比对,以鉴定推定的生物标志物
候选人,以实现我们的最终目标,并建立一个生物标志物面板组织和辐射特异性损伤
(Aim 3)。这项研究与急性和慢性辐射效应有广泛的相关性,它集中体现了复杂的
辐射损伤组织与免疫稳态之间的相互作用。我们注意到挑战
当比较X射线和中子使用体内照射时,
研究晚期发病率因此,我们组建了一个团队,结合放射生物学的专业知识,
免疫学、miRNA分析、辐射物理学和剂量学、兽医护理和统计学,
这项研究的各个方面。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Dorthe Schaue其他文献
Dorthe Schaue的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Dorthe Schaue', 18)}}的其他基金
Acute radiation injury alters microRNA profiles that predict late tissue-specific damage
急性辐射损伤改变了预测晚期组织特异性损伤的 microRNA 谱
- 批准号:
10557205 - 财政年份:2020
- 资助金额:
$ 66.14万 - 项目类别:
Acute radiation injury alters microRNA profiles that predict late tissue-specific damage
急性辐射损伤改变了预测晚期组织特异性损伤的 microRNA 谱
- 批准号:
10329926 - 财政年份:2020
- 资助金额:
$ 66.14万 - 项目类别:
Myeloid reprogramming in response to acute radiation tissue damage
响应急性辐射组织损伤的骨髓重编程
- 批准号:
10112746 - 财政年份:2019
- 资助金额:
$ 66.14万 - 项目类别:
Visualizing radiation-induced tumor immune responses
可视化辐射诱导的肿瘤免疫反应
- 批准号:
9908059 - 财政年份:2019
- 资助金额:
$ 66.14万 - 项目类别:
Myeloid reprogramming in response to acute radiation tissue damage
响应急性辐射组织损伤的骨髓重编程
- 批准号:
10583509 - 财政年份:2019
- 资助金额:
$ 66.14万 - 项目类别:
Myeloid reprogramming in response to acute radiation tissue damage
响应急性辐射组织损伤的骨髓重编程
- 批准号:
10375367 - 财政年份:2019
- 资助金额:
$ 66.14万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 66.14万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 66.14万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 66.14万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 66.14万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 66.14万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 66.14万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 66.14万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 66.14万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 66.14万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 66.14万 - 项目类别:
Research Grant