Role of WASP/WIP Complex in T Cell Function
Role of WASP/WIP Complex in T Cell Function
批准号:
8147993
负责人:
RAIF SALIM GEHA
金额:
$37.03万
依托单位国家:
美国
项目类别:
财政年份:
2010
资助国家:
美国
项目状态:
已结题
起止时间:
2010-09-01 至 2013-08-31
关键词:
ActinsAutoimmunityB-LymphocytesBindingBlood PlateletsCell physiologyCellsChemotaxisCleaved cellColitisComplexCytoskeletonDataDefectDendritic CellsDiseaseDropsEczemaFunctional disorderGenesGenetically Engineered MouseHomingHumanImmunologic Deficiency SyndromesIn VitroInbred BALB C MiceIndividualInfectionInterleukin-2Knock-in MouseLeadLinkMalignant lymphoid neoplasmMindMusMutationNormal RangePathogenesisPatientsPeptidesPeripheralPhenotypePlayPredispositionProliferatingProtein BindingProteinsReceptor SignalingRecurrenceRoleSignal TransductionStromal Cell-Derived Factor 1StructureSurfaceT-LymphocyteTestingThrombocytopeniaTransgenic OrganismsWASP proteinWiskott-Aldrich Syndromecomplex IVin vivomolecular pathologymonocytemouse Waspip proteinmutantnovelprotein complexprotein functionreconstitutionresearch studyresponse
中文摘要
T细胞功能障碍有助于Wiskott-Aldrich综合征(WAS)患者对
英文摘要
T cell dysfunction contributes to the susceptibility of patients with the Wiskott-Aldrich syndrome (WAS) to
infection, autoimmunity and lymphoid malignancy. This project probes the function of WASP and its partner
WASP interacting protein WIP in T cells.
Most of WASP is complexed with WIP in T cells. WASP levels of drop to ~10% of normal in T cells from
WIP KO mice and from WAS patients with mutations that disrupt WIP binding, suggesting that WIP
stabilizes WASP. Our Preliminary data show that the hierarchy of T cell dysfunction is WASP/WIP
DKOWIP KOWASP KO, bearing in mind that since WASP levels are low in WIP KO T cells the individual
contribution of WIP to the WIP KO phenotype is unknown.
Our overall hypothesis is that WIP and WASP function in T cells both as a complex and independently. To
test our hypothesis we propose to use genetically engineered mice which selectively lack WIP, WASP or
both, or in which the WASP/WIP complex is disrupted. We will:
1. Compare T cells from WASP/WIP DKO mice to T cells from WT mice to define the combined role of WIP
and WASP. In addition, comparison with WASP KO T cells would define WIP functions that may be
independent of WASP.
2. Reconstitute T cells from WIP KO mice with a peptide that consists of the WASP binding domain (WBD)
of WIP in order to restore WASP levels, and thus generate WIP deficient/WASP expressing T cells. We will
compare T cells from these mice to WT T cells to define the role of WIP.
3. Disrupt the WASP/WIP complex expressing the WBD in WT T cells to test the hypothesis that there is a
subset of signaling functions that is dependent on the WASP/WIP complex.
4. Examine the structure and function of T cells from knockin mice that express a WIP mutant that lacks the
actin-binding region to define the role of WIP binding to actin in the subcellular localization and function of
the WASP/WIP complex.
The results of the proposed experiments in the mouse will aid in our understanding of the pathogenesis of
WAS in humans and should lead to novel treatments for this disease.
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海外基金