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.
威斯科特-奥尔德里奇综合征 (WAS) 是一种严重的免疫缺陷,由 WASP 突变引起,
属于控制肌动蛋白从头成核的蛋白质家族。目前尚不清楚是否存在体液缺陷
在 WAS 患者和 WASP-/- 小鼠中观察到的免疫反应反映了 WASP 对 B 细胞的内在 B 细胞作用
分化、功能,以及 N-WASP 是否在这些过程中发挥补偿作用。
我们将检验 WASP 和/或 N-WASP 表达缺失影响 B 淋巴细胞的假设
以细胞固有的方式成熟、归巢和发挥作用。
为此,我们将研究人类和 WASP+ 细胞和 WASP- 细胞之间的体内竞争模型。
老鼠。我们还将开发条件敲除模型,其中 WASP 和/或 N-WASP 的表达是
B淋巴细胞中消融。具体来说,我们将:
1)通过体内分析,分析WASP在B细胞发育成熟中的作用
小鼠和人类的竞争模型。
将分析携带者中 WASP+ 和 WASP- 细胞中记忆和幼稚 B 细胞的比例
XLT。我们还将分析 WASP 在生发中心反应和体细胞超突变中的作用
对 WASP+/- 小鼠和 B 细胞中 N-WASP 表达缺失的 WASP+/- 小鼠进行免疫。
2) 检验 B 细胞特异性缺乏 WASP 和/或 N-WASP 影响 B 细胞成熟的假设,
体内归巢和功能。
为此,我们将开发 B 细胞 WASP 缺陷的条件模型。我们将测试
B 细胞的外周分布和归巢,以及 B 细胞特异性缺乏的小鼠对免疫的反应
WASP 和/或 N-WASP。我们将分析具有 B 细胞特异性 WASP 缺陷的小鼠对
侵袭性肺炎链球菌感染,并探讨 IgM 记忆 B 细胞数量可能存在的缺陷
WASP基因突变患者。
3) 测试 B 细胞特异性缺乏 WASP 和/或 N-WASP 会影响体外 B 细胞功能的假设。
为此,将在来自 B 细胞的体外研究趋化性、激活和类别转换重组。
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有助于更好地了解 WAS 的生物学,并将
对于开发 WAS 新型治疗方法(包括基因治疗)非常重要。
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:
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Characterization of a novel combined immunodeficiency with skeletal dysplasia
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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
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8686738 - 财政年份:2012
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使用患者来源的 iPS 细胞建模和纠正人类 SCID
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8342843 - 财政年份:2012
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使用患者来源的 iPS 细胞建模和纠正人类 SCID
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8495926 - 财政年份:2012
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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:
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
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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
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7873273 - 财政年份:2010
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7614099 - 财政年份:2009
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$ 21.49万 - 项目类别:
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