Survival Function of the Fadd-Caspase-8-Flip Complex - MERIT Extension
Survival Function of the Fadd-Caspase-8-Flip Complex - MERIT Extension
批准号:
10581475
负责人:
DOUGLAS R GREEN
金额:
$45.5万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-05-01 至 2027-04-30
关键词:
AdultAnimalsApoptosisApoptoticBone MarrowCASP8 geneCell DeathCell Death ProcessCellsComplexDataDefectDevelopmentDiseaseEmbryoGenetic ModelsHomeostasisIn VitroInflammatoryInterferonsInvestigationLearningLigandsLoxP-flanked alleleMediatingMusPathogenesisPathway interactionsPhosphotransferasesPlayProcessPublishingRIPK1 geneRIPK3 geneRegulationRoleSignal TransductionSyndromeTNF geneTNFRSF6 geneTNFSF6 geneautoimmune lymphoproliferative syndromedesignexperimental studyinsightmutantnovelrecruit
中文摘要
其中FADD-半胱天冬酶-8-FLIP复合物控制RIPK 3-MLKL介导的细胞死亡的坏死性凋亡是一种细胞凋亡。
由TNF和相关配体参与的炎性细胞死亡过程,TLR信号传导(涉及TRIF)
和干扰素。坏死性凋亡与发育和成人体内平衡有关。通过基因
模型和基于细胞的体外实验,我们已经了解到RIPK 1在坏死性凋亡中起着相反的作用,
在不同的环境中促进或抑制该过程。我们的中心假设,基于我们发表的
和广泛的初步数据,是FADD-半胱天冬酶-8-FLIP与RIPK 1-RIPK 3-MLKL的相互作用,
在炎症性疾病的调节中至关重要。基于这一假设,我们将问:1。
FADD-caspase-8-FLIP和RIPK 1如何在RIPK 3的调节中发挥作用?在这里,我们将探讨
RIPK 1在正性和负性调节RIPK 3和坏死性凋亡中的作用,两者都是通过招募FADD-
caspase-8-FLIP对坏死体复合物的抑制作用及其激酶失活形式的抑制功能。基于细胞
体外研究将阐明RIPK 1是如何执行这些功能的,我们将把这些应用于我们的悖论。
发现RIPK 1的激酶失活突变体可能无法挽救FADD或caspase-1的胚胎致死性,
8-缺陷小鼠2. FADD-半胱天冬酶-8-FLIP和RIPK 1的生存功能在人肝癌细胞中是如何发挥作用的?
炎症性疾病?在这里,我们将采用新的遗传模型(具有RIPK 3的floxed等位基因的小鼠,
具有caspase-8的存活但不具有凋亡功能的caspase-8突变体)来探索几种
已经表明涉及凋亡或坏死性凋亡的炎性病症。3.怎么
FADD-caspase-8-FLIP和RIPK 3-MLKL抑制ALPS?自身免疫性淋巴增生
在CD 95/CD 95 L缺陷的背景下,ALPS综合征(ALPS)的研究已经进行了几十年,
这种疾病的发病机制,很大程度上是由于CD 95缺陷的骨髓不能将CD 95转移到骨髓。
综合征相比之下,我们已经发现,在半胱天冬蛋白8-/-ripk 3-/-动物中的ALPS容易转移到野生型细胞中。
受惠人士我们将利用这一点,以及我们新的遗传模型,探索这种综合征。的
建议的研究,自始至终,旨在提供对RIPK 1功能的更深入理解
与FADD-半胱天冬酶-8-FLIP和RIPK 3-MLKL的相互作用,这是两种不同形式细胞的相互作用途径
死亡通过这些正在进行的调查,我们将扩大我们的基本见解,如何监管
RIPK 1-RIPK 3-MLKL轴通过FADD-caspase-8-FLIP的功能对炎症性疾病的影响。
英文摘要
Necroptosis, in which the FADD-caspase-8-FLIP complex controls RIPK3-MLKL-mediated cell death, is an
inflammatory cell death process that is engaged by TNF and related ligands, TLR signaling (involving TRIF)
and interferons. Necroptosis has been implicated in development and adult homeostasis. Through genetic
models and in vitro cell-based experiments, we have learned that RIPK1 plays contrasting roles in necroptosis,
either promoting or inhibiting the process in different settings. Our central hypothesis, based on our published
and extensive preliminary data, is that the interaction of FADD-caspase-8-FLIP with RIPK1-RIPK3-MLKL is
fundamentally important in the regulation of inflammatory diseases. Based on this hypothesis, we will ask: 1.
How do FADD-caspase-8-FLIP and RIPK1 function in the regulation of RIPK3? Here we will explore the
roles of RIPK1 in positively and negatively regulating RIPK3 and necroptosis, both by recruiting FADD-
caspase-8-FLIP to the necrosome complex and the inhibitory function of its kinase-inactive form. Cell-based in
vitro studies will elucidate how RIPK1 performs these functions, and we will apply these to our paradoxical
finding that the kinase-inactive mutant of RIPK1 may not rescue the embryonic lethality of FADD- or caspase-
8-deficient mice. 2. How do the survival functions of FADD-caspase-8-FLIP and RIPK1 function in
inflammatory disease? Here we will employ novel genetic models (mice with a floxed allele of RIPK3, mice
harboring a caspase-8 mutant with the survival but not the apoptotic function of caspase-8) to explore several
inflammatory conditions in which involvement of apoptosis or necroptosis has been suggested. 3. How do
FADD-caspase-8-FLIP and RIPK3-MLKL suppress ALPS? While autoimmune lymphoproliferative
syndrome (ALPS) has been studied for decades in the context of CD95/CD95L defects, little is known about
the pathogenesis of this disease, largely due to an inability of CD95-deficient bone marrow to transfer the
syndrome. In contrast, we have found that ALPS in casp8-/-ripk3-/- animals is readily transferred to wt
recipients. We will exploit this, and our novel genetic models, in the exploration of this syndrome. The
proposed studies, throughout, are designed to provide a deeper understanding into the functions of RIPK1
interactions with FADD-caspase-8-FLIP, and RIPK3-MLKL, two interacting pathways to different forms of cell
death. Through these ongoing investigations, we will extend our fundamental insights into how the regulation
of the RIPK1-RIPK3-MLKL axis by the function of FADD-caspase-8-FLIP impacts on inflammatory diseases.
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DOI:
10.1016/j.isci.2023.107879
发表时间:
2023-10-20
期刊:
ISCIENCE
影响因子:
5.8
作者:
[Wahida, Adam, Schmaderer, Christoph, Buettner-Herold, Maike, Branca, Caterina, Donakonda, Sainitin, Haberfellner, Flora, Torrez, Carlos, Schmitz, Jessica, Schulze, Tobias, Seibt, Tobias, Oellinger, Rupert, Engleitner, Thomas, Haller, Bernhard, Steiger, Katja, Guenthner, Roman, Lorenz, Georg, Yabal, Monica, Bachmann, Quirin, Braunisch, Matthias C., Moog, Philipp, Matevossian, Edouard, Assfalg, Volker, Thorban, Stefan, Renders, Lutz, Spath, Martin R., Mueller, Roman-Ulrich, Stippel, Dirk L., Weichert, Wilko, Slotta-Huspenina, Julia, von Vietinghoff, Sibylle, Viklicky, Ondrej, Green, Douglas R., Rad, Roland, Amann, Kerstin, Linkermann, Andreas, Brasen, Jan Hinrich, Heemann, Uwe, Kemmner, Stephan]
通讯作者:
Kemmner, Stephan
DOI:
10.1007/978-1-4939-8754-2_7
发表时间:
2018
期刊:
Methods in molecular biology
影响因子:
--
作者:
[D. Rodriguez;D. Green]
通讯作者:
D. Rodriguez;D. Green
DOI:
10.1038/icb.2010.37
发表时间:
2010-10
期刊:
IMMUNOLOGY AND CELL BIOLOGY
影响因子:
4
作者:
[Janssen, Edith M., Lemmens, Ed E., Gour, Naina, Reboulet, Rachel A., Green, Douglas R., Schoenberger, Stephen P., Pinkoski, Michael J.]
通讯作者:
Pinkoski, Michael J.
DOI:
10.1371/journal.ppat.1001014
发表时间:
2010-07-22
期刊:
PLoS pathogens
影响因子:
6.7
作者:
[McAuley JL, Chipuk JE, Boyd KL, Van De Velde N, Green DR, McCullers JA]
通讯作者:
McCullers JA
DOI:
10.4049/jimmunol.1601294
发表时间:
2016-11-15
期刊:
Journal of immunology (Baltimore, Md. : 1950)
影响因子:
--
作者:
[Peterson LW, Philip NH, Dillon CP, Bertin J, Gough PJ, Green DR, Brodsky IE]
通讯作者:
Brodsky IE
共 15 条
Survival Function of the Fadd-Caspase-8-Flip Complex - MERIT Extension
-
批准号:10295823
-
项目类别:
-
资助金额:$45.5万
-
财政年份:2022
-
负责人:DOUGLAS R GREEN
-
依托单位:
Mechanisms of Regulated Cell Death
-
批准号:10684665
-
项目类别:
-
资助金额:$104.11万
-
财政年份:2018
-
负责人:DOUGLAS R GREEN
-
依托单位:
Mechanisms of Regulated Cell Death
-
批准号:10229410
-
项目类别:
-
资助金额:$107.7万
-
财政年份:2018
-
负责人:DOUGLAS R GREEN
-
依托单位:
Mechanisms of Regulated Cell Death
-
批准号:9756352
-
项目类别:
-
资助金额:$104.47万
-
财政年份:2018
-
负责人:DOUGLAS R GREEN
-
依托单位:
Mechanisms of Regulated Cell Death
-
批准号:9978747
-
项目类别:
-
资助金额:$107.7万
-
财政年份:2018
-
负责人:DOUGLAS R GREEN
-
依托单位:
Mechanisms of Regulated Cell Death
-
批准号:10451550
-
项目类别:
-
资助金额:$105.55万
-
财政年份:2018
-
负责人:DOUGLAS R GREEN
-
依托单位:
RIPK-dependent necrosis in development and cancer
-
批准号:8345283
-
项目类别:
-
资助金额:$36.31万
-
财政年份:2012
-
负责人:DOUGLAS R GREEN
-
依托单位:
To the edge of necroptosis and back
-
批准号:9318899
-
项目类别:
-
资助金额:$42.63万
-
财政年份:2012
-
负责人:DOUGLAS R GREEN
-
依托单位:
RIPK-dependent necrosis in development and cancer
-
批准号:8507184
-
项目类别:
-
资助金额:$34.13万
-
财政年份:2012
-
负责人:DOUGLAS R GREEN
-
依托单位:
RIPK-dependent necrosis in development and cancer
-
批准号:8856171
-
项目类别:
-
资助金额:$36.31万
-
财政年份:2012
-
负责人:DOUGLAS R GREEN
-
依托单位:
BCL2 Family Protein Interactions In Cellular Survival States
-
批准号:8895111
-
项目类别:
-
资助金额:$33.82万
-
财政年份:2011
-
负责人:DOUGLAS R GREEN
-
依托单位:
BCL-2 Family Protein interactions in Apoptosis
-
批准号:8209048
-
项目类别:
-
资助金额:$33.25万
-
财政年份:2011
-
负责人:DOUGLAS R GREEN
-
依托单位:
BCL-2 Family Protein interactions in Apoptosis
-
批准号:8401896
-
项目类别:
-
资助金额:$32.09万
-
财政年份:2011
-
负责人:DOUGLAS R GREEN
-
依托单位:
BCL-2 Family Protein interactions in Apoptosis
-
批准号:8034423
-
项目类别:
-
资助金额:$33.01万
-
财政年份:2011
-
负责人:DOUGLAS R GREEN
-
依托单位:
Mechanisms of Stress Induced Apoptosis in T-Cells
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批准号:7937305
-
项目类别:
-
资助金额:$9.93万
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财政年份:2009
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负责人:DOUGLAS R GREEN
-
依托单位:
DISRUPTION OF MITOCHONDRIAL FUNCTION DURING APOPTOSIS
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批准号:7722338
-
项目类别:
-
资助金额:$0.32万
-
财政年份:2008
-
负责人:DOUGLAS R GREEN
-
依托单位:
MECHANISMS OF APOPTOSIS
-
批准号:7601018
-
项目类别:
-
资助金额:$1.09万
-
财政年份:2007
-
负责人:DOUGLAS R GREEN
-
依托单位:
DISRUPTION OF MITOCHONDRIAL FUNCTION DURING APOPTOSIS
-
批准号:7601685
-
项目类别:
-
资助金额:$0.18万
-
财政年份:2007
-
负责人:DOUGLAS R GREEN
-
依托单位:
DISRUPTION OF MITOCHONDRIAL FUNCTION DURING APOPTOSIS
-
批准号:7601036
-
项目类别:
-
资助金额:$1.09万
-
财政年份:2007
-
负责人:DOUGLAS R GREEN
-
依托单位:
MECHANISMS OF APOPTOSIS
-
批准号:7358035
-
项目类别:
-
资助金额:$1.02万
-
财政年份:2006
-
负责人:DOUGLAS R GREEN
-
依托单位:
海外基金