Role of WASP and N-WASP in B cell maturation, homing and function
WASP 和 N-WASP 在 B 细胞成熟、归巢和功能中的作用
基本信息
- 批准号:8148002
- 负责人:
- 金额:$ 21.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-09-01 至 2013-08-31
- 项目状态:已结题
- 来源:
- 关键词:ActinsAffectAllogenicAntibodiesAntibody FormationAntigensAutoimmunityAutologousB Cell ProliferationB cell differentiationB-Cell ActivationB-Cell DevelopmentB-LymphocytesBiochemicalBiologyBlood PlateletsBone MarrowCD19 geneCell MaturationCell physiologyCellsChemotaxisChimerismCicatrixClinicalComplexCytoskeletonDataDefectDendritic CellsDevelopmentDisadvantagedDoseEczemaEventGene MutationGene TargetingGenerationsGenesGenetic VariationHematopoieticHematopoietic Stem Cell TransplantationHomingHumanHumoral ImmunitiesIgEImmuneImmunizationImmunoglobulin AImmunoglobulin Class SwitchingImmunoglobulin MImmunoglobulin Somatic HypermutationImmunoglobulin Switch RecombinationIn VitroInfectionKnock-outKnockout MiceLeukocytesLinkMS4A1 geneMalignant NeoplasmsMemoryMemory B-LymphocyteMicrofilamentsModelingMolecular ConformationMusMutationPatientsPatternPeripheralPlasmablastPlayPneumococcal InfectionsPolysaccharidesPredispositionProcessProtein FamilyProteinsReactionRestRiskRoleSerumSpleenStem cellsStreptococcus pneumoniaeStructure of germinal center of lymph nodeSystemT-Independent AntigensT-LymphocyteTestingThrombocytopeniaWiskott-Aldrich SyndromeX Inactivationbaseblastocystcell typechemokinegene therapyhumoral immunity deficiencyin vivomacrophagenovelperipheral bloodprogenitorresponse
项目摘要
The Wiskott-Aldrich syndrome (WAS) is a severe immune deficiency, caused by mutations of WASP, that
belongs to a family of proteins that control de novo actin nucleation. It is unclear whether defects in humoral
immunity observed in patients with WAS and in WASP-/- mice reflect a B-cell intrinsic role of WASP for B cell
differentiation, and function, and whether N-WASP may play a compensatory role in these processes.
We will test the hypothesis that lack of expression of WASP and/or N-WASP affects B lymphocyte
maturation, homing and function in a cell-intrinsic fashion.
To this purpose, we will study in vivo competition models between WASP+ and WASP- cells in humans and
mice. We will also develop conditional knock-out models in which expression of WASP and/or N-WASP is
ablated in B lymphocytes. Specifically, we will:
1) analyze the role of WASP in B cell development and maturation, through the analysis of in vivo
competition models both in mice and in humans.
The proportion of memory and naive B cells will be analyzed among WASP+ and WASP- cells in carriers of
XLT. We will also analyze the role of WASP in germinal center reaction and somatic hypermutation following
immunization in WASP+/- mice and in WASP+/- mice in which expression of N-WASP is deleted in B cells.
2) test the hypothesis that the B-cell specific lack of WASP and/or N-WASP affects B cell maturation,
homing and function in vivo.
To this purpose, we will develop a conditional model of WASP deficiency in B cells. We will test the
peripheral distribution and homing of B cells, and response to immunization in mice with B-cell specific lack
of WASP and/or N-WASP. We will analyze susceptibility of mice with B-cell-specific deficiency of WASP to
invasive S. pneumoniae infection, and explore possible defects in the number of IgM memory B cells in
patients with WASP gene mutations.
3) test the hypothesis that the B-cell specific lack of WASP and/or N-WASP affects B cell function in vitro.
To this purpose, chemotaxis, activation and class-switch recombination will be studied in vitro in B cells from
mice with B-cell specific lack of WASP and/or N-WASP.
We anticipate that the results of .this project will allow a better understanding of the biology of WAS, and will
be important for development of novel forms of treatment of WAS, including gene therapy.
Wiskott-Aldrich综合征(WAS)是一种严重的免疫缺陷,由WASP突变引起,
属于控制从头肌动蛋白成核的蛋白质家族。目前尚不清楚体液免疫缺陷是否
在WASP患者和WASP-/-小鼠中观察到免疫反应反映了WASP对B细胞的B细胞内在作用
分化和功能,以及N-WASP是否可能在这些过程中发挥补偿作用。
我们将检验WASP和/或N-WASP表达缺乏影响B淋巴细胞的假设。
成熟、归巢和以细胞内在方式发挥功能。
为此,我们将研究人体内WASP+和WASP-细胞之间的体内竞争模型,
小鼠我们还将开发条件性敲除模型,其中WASP和/或N-WASP的表达是
在B淋巴细胞中消融。具体而言,我们将:
1)分析WASP在B细胞发育和成熟中的作用,通过体内实验分析WASP对B细胞发育和成熟的影响。
在小鼠和人类中的竞争模型。
将在WASP+和WASP-细胞中分析记忆和幼稚B细胞的比例。
XLT。我们还将分析WASP在老年中枢反应和体细胞超变中的作用,
在WASP+/-小鼠和其中N-WASP表达在B细胞中缺失的WASP+/-小鼠中进行免疫。
2)检验WASP和/或N-WASP的B细胞特异性缺乏影响B细胞成熟的假设,
归巢和体内功能。
为此,我们将开发一种B细胞中WASP缺乏的条件模型。我们将测试
B细胞特异性缺乏小鼠外周血B细胞的分布、归巢及免疫应答
WASP和/或N-WASP。我们将分析B细胞特异性WASP缺乏的小鼠对以下疾病的易感性
入侵S. pneumoniae感染,并探讨IgM记忆B细胞数量的可能缺陷,
WASP基因突变的患者。
3)检验WASP和/或N-WASP的B细胞特异性缺乏影响体外B细胞功能的假设。
为了这个目的,将在体外研究来自以下的B细胞中的趋化性、活化和类别转换重组:
B细胞特异性缺乏WASP和/或N-WASP的小鼠。
我们预计,该项目的结果将使我们更好地了解WAS的生物学,
对于开发WAS的新治疗形式,包括基因治疗,具有重要意义。
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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Luigi Daniele Notarangelo其他文献
Luigi Daniele Notarangelo的其他文献
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{{ truncateString('Luigi Daniele Notarangelo', 18)}}的其他基金
Characterization of a novel combined immunodeficiency with skeletal dysplasia
一种新型联合免疫缺陷伴骨骼发育不良的特征
- 批准号:
8886617 - 财政年份:2015
- 资助金额:
$ 21.49万 - 项目类别:
Characterization of a novel combined immunodeficiency with skeletal dysplasia
一种新型联合免疫缺陷伴骨骼发育不良的特征
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8995190 - 财政年份:2015
- 资助金额:
$ 21.49万 - 项目类别:
Modeling and correcting human SCID using patient-derived iPS cells
使用患者来源的 iPS 细胞建模和纠正人类 SCID
- 批准号:
8342843 - 财政年份:2012
- 资助金额:
$ 21.49万 - 项目类别:
Modeling and correcting human SCID using patient-derived iPS cells
使用患者来源的 iPS 细胞建模和纠正人类 SCID
- 批准号:
8686738 - 财政年份:2012
- 资助金额:
$ 21.49万 - 项目类别:
Modeling and correcting human SCID using patient-derived iPS cells
使用患者来源的 iPS 细胞建模和纠正人类 SCID
- 批准号:
8495926 - 财政年份:2012
- 资助金额:
$ 21.49万 - 项目类别:
In vitro differentiation of RAG1-mutated iPS cells and correction by meganuclease
RAG1 突变 iPS 细胞的体外分化和大范围核酸酶校正
- 批准号:
8079018 - 财政年份:2010
- 资助金额:
$ 21.49万 - 项目类别:
Reprogramming of fibroblasts to pluripotency- a new tool to study Primary Immunod
成纤维细胞重编程为多能性——研究初级免疫的新工具
- 批准号:
7873273 - 财政年份:2010
- 资助金额:
$ 21.49万 - 项目类别:
In vitro differentiation of RAG1-mutated iPS cells and correction by meganuclease
RAG1 突变 iPS 细胞的体外分化和大范围核酸酶校正
- 批准号:
7947212 - 财政年份:2010
- 资助金额:
$ 21.49万 - 项目类别:
Reprogramming of fibroblasts to pluripotency- a new tool to study Primary Immunod
成纤维细胞重编程为多能性——研究初级免疫的新工具
- 批准号:
8022818 - 财政年份:2010
- 资助金额:
$ 21.49万 - 项目类别:
Murine gene knock-in models fo Omenn Syndrome and leaky SCID
Omenn 综合征和渗漏 SCID 的小鼠基因敲入模型
- 批准号:
7614099 - 财政年份:2009
- 资助金额:
$ 21.49万 - 项目类别:
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