Mechanisms of Control of Lymphocyte Activation and Proliferation by a Critical Signaling Integrator
关键信号整合器控制淋巴细胞激活和增殖的机制
基本信息
- 批准号:10304147
- 负责人:
- 金额:$ 43.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-12-01 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:AllelesAntigen ReceptorsAntigensB Cell ProliferationB-Cell ActivationB-Cell Antigen ReceptorB-Cell LymphomasB-LymphocytesBehaviorBromodomainBypassCD69 antigenCRISPR screenCell CountCellsComplexCritical PathwaysDevelopmentDiseaseElementsEtiologyGenesGeneticGrowthHumanImmuneImmune responseInfectionKineticsKnock-in MouseKnockout MiceKnowledgeLesionLeukocytesLymphocyteLymphocyte ActivationLymphocyte FunctionLymphomaLymphomagenesisMalignant NeoplasmsMediatingMolecularMolecular TargetMusMutationOncogenicOutputPathogenicityPathway interactionsPatientsPhysiologicalProcessProteinsReceptor CellReceptor SignalingRoleSamplingScaffolding ProteinSeverity of illnessSignal PathwaySignal TransductionSignaling MoleculeSignaling ProteinT-Cell ReceptorT-LymphocyteTestingWorkadaptive immune responsecell behaviorcofactordesigngain of functiongenome-wideimmune system functionimprovedin vivoinhibitorinsightlarge cell Diffuse non-Hodgkin&aposs lymphomalymphocyte proliferationnovelnovel therapeuticspathogenpreventprotein functionreceptorrecruitscaffoldtherapy design
项目摘要
PROJECT SUMMARY/ABSTRACT
Antigen receptor signaling to NF-κB is a highly regulated, critical pathway for B and T lymphocyte activation
during the adaptive immune response. NF-κB controls many genes required for lymphocyte function including
genes that promote proliferation and survival. The inappropriate activation of NF-κB is associated with multiple
lymphomas, which frequently acquire mutations in signaling molecules that elicit their receptor-independent
constitutive NF-κB activity. CARD11 is a key scaffold protein that functions in both T cell receptor and B cell
receptor pathways to transmit signals from the engaged receptor to the activation of the IKK complex and NF-
κB. Aberrant CARD11-dependent signaling is required for the dysregulated proliferation of the activated B cell-
like (ABC) subtype of Diffuse Large B Cell Lymphoma (DLBCL), and mutations in CARD11, which
hyperactivate the protein, are found in ~10% of patient samples of ABC DLBCL. Previous work has established
that during normal signaling, CARD11 undergoes a transition from an inactive to an active signaling scaffold
that recruits several signaling cofactors into a complex that induces IKK activity. An Inhibitory Domain (ID) in
CARD11 controls this transition; it keeps CARD11 inactive in the basal state, but receives signals from the
engaged receptor that neutralize its inhibitory action and allow CARD11 to signal. Lymphoma-associated
mutations in CARD11 bypass normal activation and convert CARD11 into a constitutively active signaling
scaffold. However, it remains poorly understood how during normal antigen receptor signaling CARD11 is
converted to its active state, how precisely normal and oncogenic forms of CARD11 signal to the IKK complex
to activate NF-κB, and how DLBCL-associated gain-of-function CARD11 alleles achieve the transformation of
normal B cells into lymphoma. In this application we will 1) investigate how signaling potential and cooperating
mutations determine the extent of oncogenic CARD11-mediated aberrant B cell proliferation in vivo; 2)
investigate the role of a newly identified factor required for CARD11 activity in normal and oncogenic antigen
receptor signaling; and 3) dissect determinants required for several steps in the CARD11 signaling cycle. Our
studies will advance understanding of the mechanisms of antigen receptor signaling during lymphocyte
activation, illuminate how signaling proteins, especially scaffolds, achieve signal-induced activation during
normal physiological behavior, and improve our understanding of how the combination of genetic lesions found
in lymphoma determines disease severity. Our studies should reveal a previously unrecognized molecular
target for the development of new therapies designed to treat NF-κB-dependent cancers and other diseases
that result from aberrant immune cell behavior.
项目摘要/摘要
抗原受体信号传导至核因子-κB是B和T淋巴细胞激活的一条受高度调控的关键途径
在适应性免疫反应过程中。核因子-κB控制许多淋巴细胞功能所需的基因,包括
促进增殖和存活的基因。核因子-κB的异常激活与多个
淋巴瘤,它经常在信号分子上获得突变,从而引发其受体非依赖性
组成性核因子-κB活性。CARD11是一种关键的支架蛋白,在T细胞受体和B细胞中都有功能
受体途径将信号从参与的受体传递到IKK复合体和核因子的激活
κB。激活的B细胞的异常增殖需要依赖于CARD11的信号。
类似弥漫性大B细胞淋巴瘤(DLBCL)的(ABC)亚型,以及CARD11的突变,其中
在大约10%的ABC DLBCL患者样本中发现了这种蛋白的过度激活。之前的工作已经确立了
在正常的信号过程中,CARD11经历了从非活动的信号支架到活动的信号支架的转变
这将几个信号辅助因子招募到一个诱导IKK活动的复合体中。中的一个抑制域(ID)
CARD11控制这一转换;它使CARD11在基本状态下保持非活动状态,但从
激活的受体,中和其抑制作用,并允许CARD11信号。淋巴瘤相关
CARD11的突变绕过了正常的激活,将CARD11转化为结构性活跃的信号
脚手架。然而,在正常的抗原受体信号转导过程中,CARD11是如何发生的,目前还知之甚少。
转换到其活性状态,CARD11信号的正常和致癌形式如何准确地传递给IKK复合体
激活核因子-κB,以及DLBCL相关的功能增益-CARD11等位基因如何实现
正常的B细胞转化为淋巴瘤。在本申请中,我们将1)调查信号潜力和合作
突变决定癌基因CARD11介导的体内异常B细胞增殖的程度;2)
研究正常和致癌抗原中CARD11活性所需的一个新发现的因子的作用
受体信号转导;3)剖析CARD11信号周期中几个步骤所需的决定因素。我们的
研究将促进对淋巴细胞中抗原受体信号机制的理解
激活,阐明信号蛋白,特别是支架,如何实现信号诱导的激活
正常的生理行为,并提高我们对如何发现组合遗传损伤的理解
淋巴瘤的严重程度决定了疾病的严重性。我们的研究应该会揭示一种以前未被发现的分子
开发用于治疗依赖于NF-κB的癌症和其他疾病的新疗法的目标
这是由于免疫细胞行为异常造成的。
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)
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Joel L Pomerantz其他文献
Joel L Pomerantz的其他文献
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{{ truncateString('Joel L Pomerantz', 18)}}的其他基金
Targeting a Membrane Protease that Controls NK Cell Maturation
靶向控制 NK 细胞成熟的膜蛋白酶
- 批准号:
10631217 - 财政年份:2022
- 资助金额:
$ 43.64万 - 项目类别:
Targeting a Membrane Protease that Controls NK Cell Maturation
靶向控制 NK 细胞成熟的膜蛋白酶
- 批准号:
10506509 - 财政年份:2022
- 资助金额:
$ 43.64万 - 项目类别:
Mechanisms of Control of Lymphocyte Activation and Proliferation by a Critical Signaling Integrator
关键信号整合器控制淋巴细胞激活和增殖的机制
- 批准号:
10063977 - 财政年份:2019
- 资助金额:
$ 43.64万 - 项目类别:
Mechanisms of Control of Lymphocyte Activation and Proliferation by a Critical Signaling Integrator
关键信号整合器控制淋巴细胞激活和增殖的机制
- 批准号:
10528445 - 财政年份:2019
- 资助金额:
$ 43.64万 - 项目类别:
Regulation of CARD11 signaling in normal and dysregulated lymphocyte development
CARD11 信号在正常和失调淋巴细胞发育中的调节
- 批准号:
8704412 - 财政年份:2013
- 资助金额:
$ 43.64万 - 项目类别:
Regulation of CARD11 signaling in normal and dysregulated lymphocyte development
CARD11 信号在正常和失调淋巴细胞发育中的调节
- 批准号:
9056446 - 财政年份:2013
- 资助金额:
$ 43.64万 - 项目类别:
Regulation of CARD11 signaling in normal and dysregulated lymphocyte development
CARD11 信号在正常和失调淋巴细胞发育中的调节
- 批准号:
8829795 - 财政年份:2013
- 资助金额:
$ 43.64万 - 项目类别:
Regulation of CARD11 signaling in normal and dysregulated lymphocyte development
CARD11 信号在正常和失调淋巴细胞发育中的调节
- 批准号:
8554256 - 财政年份:2013
- 资助金额:
$ 43.64万 - 项目类别:
Motor protein regulation of T cell receptor signaling
T 细胞受体信号传导的运动蛋白调节
- 批准号:
8099462 - 财政年份:2009
- 资助金额:
$ 43.64万 - 项目类别:
Motor protein regulation of T cell receptor signaling
T 细胞受体信号传导的运动蛋白调节
- 批准号:
7648345 - 财政年份:2009
- 资助金额:
$ 43.64万 - 项目类别:
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