Cell Death Pathways and Heart Transplant Rejection
细胞死亡途径和心脏移植排斥
基本信息
- 批准号:10162490
- 负责人:
- 金额:$ 55.08万
- 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:2017-06-01 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAllograftingAnimal ModelAnimalsAntigen-Presenting CellsAntigensApoptosisB-LymphocytesCASP8 geneCell DeathCellsChronicClinicalComplementComplement ActivationDataDevelopmentDonor personEnd stage renal failureEpidemiologyFailureFunctional disorderGraft RejectionGraft SurvivalHealthHeart TransplantationHomologous TransplantationHumanImmunityInflammationInflammation MediatorsInflammatoryInjuryInnate Immune ResponseIschemiaKidney TransplantationKnock-inKnock-outLaboratoriesLeadLectinLigandsLinkMannoseMannose Binding LectinMediatingMemoryModelingMolecularMusOrganOrgan DonorOutcomePathogenicityPathologic ProcessesPathway interactionsPatientsPatternPattern recognition receptorPharmacologyPhasePlayProductionRIPK1 geneRIPK3 geneReagentReperfusion InjuryReperfusion TherapyResistanceRiskRoleSeriesSignal TransductionT-LymphocyteTNF geneTestingTherapeutic InterventionTissue DonorsToll-like receptorsTranslatingTransplant RecipientsTransplantationTumor Necrosis Factor Receptorallograft rejectionanimal databasecell injurycomplement deficiencycytokinedelayed graft functiongraft failureheart allograftimmunogenicityimprovedinhibitor/antagonistinsightisoimmunitymouse modelnew therapeutic targetnovel strategiespost-transplantpre-clinicalpreventtargeted treatmenttransplant model
项目摘要
The long-term survival of allografts and patients receiving deceased donor organs remain poor. There
is evidence to suggest that cold ischemia (CI) and the subsequent reperfusion during transplants causes
cellular injury, which leads to an induction of T cell alloimmunity against donor tissue and ultimately graft
rejection. The mechanism by which ischemia reperfusion (IR) initiates cellular injury, the manner of the injury,
and how this injury impacts alloresponse are poorly understood. To better mimic human deceased donor
transplants, the Fairchild laboratory developed an allograft heart transplant model whereby the donor organ is
subjected to extended CI prior to transplantation followed by administration of an CTLA4Ig costimulatory
blockade. Allograft hearts subjected to CI were rejected whereas those not subjected to CI survived.
Preliminary studies using this model indicated that complement deficiency in the recipients prolonged the
survival of CI-treated allografts, correlating with reduced circulating TNFα. As TNFα is a known inducer of
necroptosis, an inflammatory cell death, additional studies showed that organs from CYLD-deficient donors,
(which are defective in necroptosis) survived longer than wild type organs whereas organs from SHARPIN-
deficient donors (which have accelerated necroptosis) were rapidly rejected. Based on these studies, we have
proposed and will test the unifying hypothesis that complement activation following CI/IR during transplants
leads to the induction of TNFα, which then induces necroptosis of cells in donor tissues. In turn, this
inflammatory cellular injury activates T cell alloimmunity to cause rejection. This collaborative study brings
together in a highly synergistic manner the unique strengths of three laboratories to address the above
hypothesis. (1) In Aim 1, we will examine the role of mannose-binding lectin (MBL)-initiated complement
activation in triggering TNF-dependent necroptosis in our allograft transplant model using MBL, TNF and
TNFRs knockouts/knockins. (2) In Aim 2, the role of the TNF cell death pathway in CI-initiated rejection will be
further dissected using donor organs derived from various knockouts/knockins of CYLD, RIPK1, RIPK3,
Caspase-8 and SHARPIN. (3) Necroptosis releases damage-associated molecular patterns (DAMPs) and thus
in Aim 3, we will examine how DAMPs are sensed by host antigen-presenting cells and how this leads to
induction of the T cell alloresponse. All three aims are highly significant, as they will provide insights into which
molecules during (1) initiation, (2) cellular injury and (3) effector phases of graft rejection may be targeted for
therapeutic blockade in transplants. The approach has strong potential to directly and positively impact
outcomes of transplant patients.
同种异体器官移植和接受已故捐献器官的患者的长期存活率仍然很低。那里
有证据表明,移植过程中的冷缺血(CI)和随后的再灌注会导致
细胞损伤,导致诱导T细胞对供体组织和最终移植物的同种免疫
拒绝。缺血再灌注(IR)引起细胞损伤的机制,损伤的方式,
这种损伤是如何影响同种异体反应的,目前还知之甚少。为了更好地模仿已故的人类捐赠者
移植,仙童实验室开发了一种同种异体心脏移植模型,通过这种模型,捐赠者的器官是
移植前接受延长的CI,然后注射CTLA4Ig共刺激分子
封锁。接受CI的同种异体心脏被排斥,而未接受CI的同种异体心脏存活。
使用该模型的初步研究表明,受者的补体缺乏延长了
脑梗塞治疗的同种异体移植物存活与循环肿瘤坏死因子α减少相关。因为肿瘤坏死因子α是一种已知的诱导剂
坏死性下垂是一种炎性细胞死亡,其他研究表明,来自CyLD缺陷捐赠者的器官,
(在坏死性下垂方面有缺陷的)比野生型器官存活的时间更长,而夏平的器官-
不足的捐赠者(加速了坏死性下垂)很快就被拒绝了。基于这些研究,我们有
提出并将检验统一的假设,即在移植过程中CI/IR后补体激活
导致肿瘤坏死因子α的诱导,继而诱导供体组织细胞的坏死性下垂。反过来,这又会导致
炎性细胞损伤激活T细胞同种免疫,导致排斥反应。这项合作研究带来了
三个实验室以高度协同的方式共同解决上述问题的独特优势
假设。(1)在目标1中,我们将研究甘露糖结合凝集素(MBL)启动的补体的作用
在我们的同种异体移植模型中,使用MBL、TNF和
TNFR基因敲除/敲打。(2)在AIM 2中,肿瘤坏死因子细胞死亡通路在CI引发的排斥反应中的作用如下
进一步利用来源于CyLD、RIPK1、RIPK3、
Caspase-8和夏平。(3)坏死性下垂释放损伤相关的分子模式(DAMP),因此
在目标3中,我们将研究宿主抗原提呈细胞是如何感知潮湿的,以及这是如何导致
诱导T细胞同种异体反应。所有这三个目标都具有非常重要的意义,因为它们将为
在(1)启动、(2)细胞损伤和(3)移植物排斥反应效应阶段的分子可能是靶点
移植中的治疗障碍。这种方法有很强的直接和积极影响的潜力
移植患者的结局。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
T follicular helper cells restricted by IRF8 contribute to T cell-mediated inflammation.
- DOI:10.1016/j.jaut.2018.09.001
- 发表时间:2019-01
- 期刊:
- 影响因子:12.8
- 作者:Zhang R;Qi CF;Hu Y;Shan Y;Hsieh YP;Xu F;Lu G;Dai J;Gupta M;Cui M;Peng L;Yang J;Xue Q;Chen-Liang R;Chen K;Zhang Y;Fung-Leung WP;Mora JR;Li L;Morse HC 3rd;Ozato K;Heeger PS;Xiong H
- 通讯作者:Xiong H
{{
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 }}
Peter Scott Heeger其他文献
Peter Scott Heeger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('Peter Scott Heeger', 18)}}的其他基金
Assessment of Biomarker Guided CNI Substitution in Kidney Transplantation
肾移植中生物标志物引导的 CNI 替代评估
- 批准号:
10654057 - 财政年份:2022
- 资助金额:
$ 55.08万 - 项目类别:
Assessment of Biomarker Guided CNI Substitution in Kidney Transplantation
肾移植中生物标志物引导的 CNI 替代评估
- 批准号:
10488428 - 财政年份:2022
- 资助金额:
$ 55.08万 - 项目类别:
Multiparametric mapping of Covid-19 immune responses in Kidney transplant recipients
肾移植受者 Covid-19 免疫反应的多参数绘图
- 批准号:
10241179 - 财政年份:2020
- 资助金额:
$ 55.08万 - 项目类别:
Biomarker Guided CNI Substitution in Kidney Transplantation
生物标志物引导肾移植中的 CNI 替代
- 批准号:
9926399 - 财政年份:2020
- 资助金额:
$ 55.08万 - 项目类别:
Targeting factor B to prevent transplant rejection
靶向因子 B 预防移植排斥
- 批准号:
9000104 - 财政年份:2015
- 资助金额:
$ 55.08万 - 项目类别:
Targeting factor B to prevent transplant rejection
靶向因子 B 预防移植排斥
- 批准号:
8873752 - 财政年份:2015
- 资助金额:
$ 55.08万 - 项目类别:
Individualizing Therapy for Kidney and Heart Transplant Recipients
肾脏和心脏移植受者的个体化治疗
- 批准号:
8100584 - 财政年份:2010
- 资助金额:
$ 55.08万 - 项目类别:
Noninvasive Markers and Transplant Outcome in Humans
人类非侵入性标志物和移植结果
- 批准号:
7919132 - 财政年份:2009
- 资助金额:
$ 55.08万 - 项目类别:
Cross-Disciplinary Training Program in Transplant Research
移植研究跨学科培训计划
- 批准号:
8662683 - 财政年份:2008
- 资助金额:
$ 55.08万 - 项目类别:
Cross-Disciplinary Training Program in Transplant Research
移植研究跨学科培训计划
- 批准号:
9284372 - 财政年份:2008
- 资助金额:
$ 55.08万 - 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:
$ 55.08万 - 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:
$ 55.08万 - 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:
$ 55.08万 - 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:
$ 55.08万 - 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:
$ 55.08万 - 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:
$ 55.08万 - 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:
$ 55.08万 - 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:
$ 55.08万 - 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:
$ 55.08万 - 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:
$ 55.08万 - 项目类别:
Research Grant