Cell Death Pathways and Heart Transplant Rejection

细胞死亡途径和心脏移植排斥

基本信息

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.
同种异体移植和接受已故供体器官的患者的长期存活率仍然很低。有

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
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了