WAVE Regulatory Complex in Primary Immunodeficiency Disease and autoimmunity
原发性免疫缺陷病和自身免疫性疾病中的 WAVE 调节复合体
基本信息
- 批准号:10789081
- 负责人:
- 金额:$ 8.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-02-10 至 2026-01-31
- 项目状态:未结题
- 来源:
- 关键词:ActinsAffectAntibody FormationAntibody ResponseAntibody-mediated protectionAntigensAutoantibodiesAutoimmunityB-Cell ActivationB-Cell Antigen ReceptorB-Cell DevelopmentB-LymphocytesB-cell receptor repertoire sequencingBacteremiaBacterial InfectionsBiological ModelsBone MarrowCRISPR/Cas technologyCell physiologyCellsChIP-seqCharacteristicsChildColorCommunitiesComplexCre-LoxPCytokine ReceptorsDevelopmentDiffusionDiseaseExhibitsFamilyFlow CytometryGene ExpressionGene TargetingGenesGenetic HeterogeneityGenetic TranscriptionGoalsGuanosine Triphosphate PhosphohydrolasesHematopoieticHomeostasisHomingHomologous ProteinHumanHumoral ImmunitiesImageImmuneImmune ToleranceImmunityImmunizationImmunoglobulin Class SwitchingImmunologic Deficiency SyndromesImmunologic ReceptorsImpairmentIndividualInfectionInfectious Skin DiseasesInflammatory Bowel DiseasesInfluenza A virusIntegrinsKnowledgeLigationLinkLymphoidMalignant lymphoid neoplasmMediatingMicroscopyMissionModelingMolecularMusMutationPatientsPlasma CellsPneumococcal PneumoniaPoint MutationPolymersPredispositionProductionPrognosisProteinsPublic HealthReceptor SignalingRecurrenceResearchResolutionRespiratory Tract InfectionsRoleSignal TransductionStreptococcus pneumoniaeSystemT-Cell ReceptorT-Independent AntigensT-LymphocyteTechnologyTestingTimeToll-like receptorsUnited States National Institutes of HealthUntranslated RNAVariantVirus Diseasesautoreactivitycell typechemokinecongenital immunodeficiencycytokineflygenetic regulatory proteingenome wide association studyhuman diseasehuman modelhumanized mousehumoral immunity deficiencyimprovedinnovationloss of functionloss of function mutationmembermigrationmortalitymouse modelnovel therapeuticspathogenpolymerizationprematurerespiratory pathogenresponserhostem cellstranscriptometranscriptome sequencingtranslational impacttwo-photonvaccination strategy
项目摘要
PROJECT SUMMARY
Of the greater than 350 Primary Immunodeficiency Diseases (PID) in humans that have been identified to date,
the molecular basis of a significant number (~100) of PIDs have yet to be defined. Recently, 9 children (4 now
deceased) from 4 independent families were identified with severe PIDs that were linked to mutations in the
NCKAP1L gene encoding for Hematopoietic protein-1 (Hem-1), a conserved hematopoietic cell-specific
component the WAVE actin regulatory complex (WRC). Affected children presented with severe recurring
respiratory and skin infections, failed antibody responses to pneumococcal immunization (characteristic of B
cell immunodeficiency), dysregulated cytokine production, and autoimmunity. Although the cellular and
molecular functions of Hem-1 orthologues in flies and worms are relatively well characterized, there is a critical
knowledge gap regarding the cell specific functions of Hem-1 in the development and functions of primary
immune cells. Our longterm goal is to overcome this knowledge gap by dissecting the cell-specific roles of
Hem-1 in the development and functions of adaptive and innate immune cells. The objective of this proposal is
to disrupt Hem-1 expression in primary murine and human B lymphocytes in a B cell-specific manner to define
the roles of Hem-1 in B cell development, protective humoral immunity, and autoimmunity. Our Specific Aims
are to utilize inducible B cell specific gene targeting in mice, and CRISPR/Cas9 mediated Hem1 deletion in
“humanized mice”, to test our central hypotheses that B cell specific disruption in Hem1 results in: (1) impaired
B cell development in part due to reduced homing and retention of developing B cell progenitors in essential
lymphoid niches;(2) absent T cell independent antibody responses resulting in crippled protective immunity to
influenza A virus and Streptococcus pneumoniae, important community acquired respiratory pathogens; and
(3) hyper-responsive B cell signaling and T-bet driven transcriptome, resulting in increased autoantibody
production. To demonstrate feasibility, we have generated innovative mouse models to emulate Hem1 PID
patients including mice with a non-coding point mutation in Hem1 (Hem1pt/pt), Hem1 null (Hem1-/-) mice,
Hem1floxed (Hem1fl/fl) mice, as well as Hem1 deficient ”humanized mice” which contain Hem1 deficient
primary human hematopoietic cells. Based on our preliminary results which strongly support our hypotheses,
we expect that the results of these studies will be highly significant and will have a high impact because they
will define for the first time, the cellular and molecular mechanisms of how loss-of-function variants in
NCLAP1L disrupt B cell development, signaling, and protective antibody-mediated immunity resulting in PID
and autoimmunity. Because of extensive genetic heterogeneity of the 4 human PID families, limited number of
patients, and concurrent infections, the development of these innovative mouse model systems are critical for
dissecting the cellular and molecular mechanisms of how mutations in Hem-1 result in PID and autoimmunity,
and to provide much needed platforms to develop and test therapies to treat and cure Hem1 deficient children.
项目总结
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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BRIAN M IRITANI其他文献
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{{ truncateString('BRIAN M IRITANI', 18)}}的其他基金
WAVE Regulatory Complex in Primary Immunodeficiency Disease and autoimmunity
原发性免疫缺陷病和自身免疫性疾病中的 WAVE 调节复合体
- 批准号:
10179093 - 财政年份:2021
- 资助金额:
$ 8.07万 - 项目类别:
WAVE Regulatory Complex in Primary Immunodeficiency Disease and autoimmunity
原发性免疫缺陷病和自身免疫性疾病中的 WAVE 调节复合体
- 批准号:
10348782 - 财政年份:2021
- 资助金额:
$ 8.07万 - 项目类别:
WAVE Regulatory Complex in Primary Immunodeficiency Disease and autoimmunity
原发性免疫缺陷病和自身免疫性疾病中的 WAVE 调节复合体
- 批准号:
10549849 - 财政年份:2021
- 资助金额:
$ 8.07万 - 项目类别:
Dissecting Hem-1 functions in B lymphocyte Development and Primary Immunodeficiency Disease
剖析 Hem-1 在 B 淋巴细胞发育和原发性免疫缺陷病中的功能
- 批准号:
10385848 - 财政年份:2021
- 资助金额:
$ 8.07万 - 项目类别:
Targeting Fnip1 to disrupt B cell development, metabolism, and transformation
靶向 Fnip1 破坏 B 细胞发育、代谢和转化
- 批准号:
8966007 - 财政年份:2014
- 资助金额:
$ 8.07万 - 项目类别:
Fnip1 Function in Lymphocyte Development, Activation and Metabolism
Fnip1 在淋巴细胞发育、激活和代谢中的功能
- 批准号:
8711871 - 财政年份:2013
- 资助金额:
$ 8.07万 - 项目类别:
Investigation of Myc Oncoprotein in B lymphocyte Development and Transformation
Myc癌蛋白在B淋巴细胞发育和转化中的研究
- 批准号:
7664581 - 财政年份:2008
- 资助金额:
$ 8.07万 - 项目类别:
Investigation of Myc Oncoprotein in B lymphocyte Development and Transformation
Myc癌蛋白在B淋巴细胞发育和转化中的研究
- 批准号:
8269009 - 财政年份:2008
- 资助金额:
$ 8.07万 - 项目类别:
Investigation of Myc Oncoprotein in B lymphocyte Development and Transformation
Myc癌蛋白在B淋巴细胞发育和转化中的研究
- 批准号:
7531220 - 财政年份:2008
- 资助金额:
$ 8.07万 - 项目类别:
Investigation of Myc Oncoprotein in B lymphocyte Development and Transformation
Myc癌蛋白在B淋巴细胞发育和转化中的研究
- 批准号:
8091302 - 财政年份:2008
- 资助金额:
$ 8.07万 - 项目类别:
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