Epigenetic mediated long-term aberrations in myeloid cells after critical illness
表观遗传介导危重病后骨髓细胞的长期畸变
基本信息
- 批准号:9893883
- 负责人:
- 金额:$ 19.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-04-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:Abnormal MonocyteAddressAffectAmericanAntibodiesAntibody titer measurementAntigensBasic ScienceBehaviorBindingC-reactive proteinCardiac Surgery proceduresCardiopulmonary BypassCellsChIP-seqCharacteristicsChromatinChronicClinicalCollecting CellCritical CareCritical IllnessCytomegalovirusDNADNA MethylationDataDeacetylationDefectEnrollmentEpigenetic ProcessEvaluationEventEvolutionExhibitsFunctional disorderFutureGene Expression RegulationGoalsHealthHomeostasisImmuneImmune systemImmunologicsImpairmentIn VitroIndividualInflammationInfluenza vaccinationInterferon Type IIInterventionInvestigationLeadLeukocytesLifeLigandsLongitudinal StudiesMacrophage ActivationMacrophage Colony-Stimulating FactorMaintenanceMeasuresMediatingMedicalMedical Care CostsMethodological StudiesMethylationModelingModificationMorbidity - disease rateMyelogenousMyeloid CellsNeoplasmsOperative Surgical ProceduresOpportunistic InfectionsOrgan failureOutcomePatient SchedulesPatientsPerformancePositioning AttributeProductionRecoveryRegulationResearchRoleSepsisSerumSerum MarkersSmall Interfering RNASocietiesStressStrokeSubfamily lentivirinaeSurvivorsSyndromeSystemTimeTraumaanergyclinical centercytokinedemethylationeconomic costepigenetic regulationepigenetic therapyepigenomefollow-uphip surgeryhistone modificationimmune functionimmunological statusimproved outcomeinflammatory markerlongitudinal analysismacrophagemonocytemortalitynoveloverexpressionpathogenpatient populationpatient subsetsprogenitorpromoterrecurrent infectionresponsesocietal coststranscription factortranscriptome sequencingtranslational medicinetrend
项目摘要
Annually over 2 million Americans are affected by critical care illnesses (CCI), with profound societal, medical
and economic costs. The cumulative morbidity from post-CCI complications ranks 4th in overall mortality in the
USA. A common denominator of CI (e.g. sepsis, trauma, and cardiopulmonary bypass (CPB)) is severe stress
imposed on the immune system. We had believed that the host's body returns to pre-insult homeostasis, but
emerging evidence suggests that recovery from a CI is lengthier than previously thought. Consequently, CI
survivors suffer from recurrent infections (e.g. cytomegalovirus (CMV)) and progressive organ failure.
Among many types of leukocytes, monocytes (MO) are pivotal in all aspects of the immune yet their functions
can be easily disrupted resulting in anergy, pathogen/neoplasm tolerance and aberrant inflammation. All of
these morbidities are seen in post-CCI/CPB individuals but it is poorly defined how abnormal MO characteristic
are maintained long-term. We hypothesize that changes in epigenetic regulation of MO and their myeloid
progenitors are pivotal in an acquired, long-term post-CCI/CPB MO immuno-aberration in certain individuals.
Our preliminary data shows that ~30% of CPB patients exhibit a newly acquired defect in MO that lasts at least
three months in vitro. This defect is related to a persistent secretion of macrophage colony stimulating factor
(M-CSF) post-CCI and epigenetic aberration of master transcription factor Pu.1. The defect correlates with
increased serum markers of inflammation (C-reactive protein (CRP), macrophage markers), and elevated titers
of αCMV antibodies. Our research plan focuses on three aims selected because of their novelty, applicability to
real-life clinical condition, potential to build a fruitful research endeavor in a future and potential to correct the
aberration Aim 1. Does CPB lead to persistent functional changes of MO associated with PU.1
activation Aim 2. Are persistent functional changes in MOs post-CPB maintained by regulation of PU.1
and downstream changes to the epigenome induced by PU.1 binding? Aim 3. Are persistent functional
changes in MOs post-CPB maintained by regulation of PU.1 and downstream changes to the
epigenome induced by PU.1 binding?
Our study addresses clinically important questions about the chronic consequences of CI and long-term
immune system regulation. The study is aligned with current trends in translational medicine. This proposal
addresses a critical issue in health maintenance and provides a potential medical interventional strategy.
每年有超过 200 万美国人受到危重护理疾病 (CCI) 的影响,这对社会、医学造成了深远的影响。
和经济成本。 CCI 后并发症的累积发病率在总体死亡率中排名第四
美国。 CI(例如败血症、创伤和体外循环 (CPB))的一个共同点是严重的压力
强加于免疫系统。我们原本相信宿主的身体会恢复到受害前的体内平衡,但是
新出现的证据表明,从脑梗塞中恢复的时间比之前想象的要长。因此,CI
幸存者遭受反复感染(例如巨细胞病毒(CMV))和进行性器官衰竭。
在许多类型的白细胞中,单核细胞 (MO) 在免疫的各个方面都至关重要,但其功能
很容易被破坏,导致无反应、病原体/肿瘤耐受性和异常炎症。所有的
这些发病现象见于 CCI/CPB 后个体,但尚不清楚 MO 特征的异常程度如何
都被长期维持。我们假设 MO 及其骨髓的表观遗传调控发生变化
祖细胞在某些个体的获得性长期 CCI/CPB MO 免疫畸变中发挥着关键作用。
我们的初步数据显示,约 30% 的 CPB 患者表现出新获得的 MO 缺陷,且该缺陷持续至少
体外三个月。这种缺陷与巨噬细胞集落刺激因子的持续分泌有关
(M-CSF) 主转录因子 Pu.1 的 CCI 后和表观遗传畸变。该缺陷与以下因素相关
炎症血清标志物(C 反应蛋白 (CRP)、巨噬细胞标志物)增加,滴度升高
αCMV 抗体。我们的研究计划侧重于三个目标,因为它们的新颖性和适用性而被选择
现实生活中的临床状况,未来建立富有成效的研究工作的潜力以及纠正问题的潜力
畸变 目标 1. CPB 是否会导致与 PU.1 相关的 MO 持续功能变化
激活 目标 2. CPB 后 MO 的持续功能变化是否通过 PU.1 的调节来维持
PU.1 结合诱导的表观基因组下游变化?目标 3. 持续发挥作用
CPB 后 MO 的变化由 PU.1 的监管和下游变化维持
PU.1 结合诱导的表观基因组?
我们的研究解决了有关 CI 的慢性后果和长期影响的临床重要问题。
免疫系统调节。该研究符合当前转化医学的趋势。这个提议
解决了健康维护中的一个关键问题,并提供了潜在的医疗干预策略。
项目成果
期刊论文数量(11)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Implications of Chronic Opioid Therapy on Perioperative Complications and Long-Term Surgical Recovery.
慢性阿片类药物治疗对围手术期并发症和长期手术恢复的影响。
- DOI:
- 发表时间:2019
- 期刊:
- 影响因子:0
- 作者:Liu,Da;DiMeglio,Matthew;DiMartino,Michael;Hajj,Jihane;Mukhanova,Maria;Rai,Karima;Winikor,Mazell;Laudanski,Krzysztof
- 通讯作者:Laudanski,Krzysztof
Humanized Mice as a Tool to Study Sepsis-More Than Meets the Eye.
- DOI:10.3390/ijms22052403
- 发表时间:2021-02-27
- 期刊:
- 影响因子:5.6
- 作者:Laudanski K
- 通讯作者:Laudanski K
Dynamic Changes in Central and Peripheral Neuro-Injury vs. Neuroprotective Serum Markers in COVID-19 Are Modulated by Different Types of Anti-Viral Treatments but Do Not Affect the Incidence of Late and Early Strokes.
- DOI:10.3390/biomedicines9121791
- 发表时间:2021-11-29
- 期刊:
- 影响因子:4.7
- 作者:Laudanski K;Hajj J;Restrepo M;Siddiq K;Okeke T;Rader DJ
- 通讯作者:Rader DJ
A disturbed balance between blood complement protective factors (FH, ApoE) and common pathway effectors (C5a, TCC) in acute COVID-19 and during convalesce.
- DOI:10.1038/s41598-022-17011-7
- 发表时间:2022-08-11
- 期刊:
- 影响因子:4.6
- 作者:Laudanski, Krzysztof;Okeke, Tony;Siddiq, Kumal;Hajj, Jihane;Restrepo, Mariana;Gullipalli, Damodar;Song, Wen-Chao
- 通讯作者:Song, Wen-Chao
Prolonged Transcriptional Consequences in Survivors of Sepsis.
- DOI:10.3390/ijms22115422
- 发表时间:2021-05-21
- 期刊:
- 影响因子:5.6
- 作者:Laudanski K;Soh J;DiMeglio M;Sullivan KE
- 通讯作者:Sullivan KE
{{
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 }}
Krzysztof Laudanski其他文献
Krzysztof Laudanski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 }}
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:
$ 19.57万 - 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:
$ 19.57万 - 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:
$ 19.57万 - 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:
$ 19.57万 - 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:
$ 19.57万 - 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:
$ 19.57万 - 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:
$ 19.57万 - 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:
$ 19.57万 - 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:
$ 19.57万 - 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:
$ 19.57万 - 项目类别:
Research Grant