The role of SERPINB1 in T cell function and its contribution to human diseases
SERPINB1在T细胞功能中的作用及其对人类疾病的贡献
基本信息
- 批准号:10659419
- 负责人:
- 金额:$ 66.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-05 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:Abnormal NeutrophilAffectAllelesAntimycobacterial AgentsApoptosisAutoimmunityBasic ScienceBiochemistryBiologicalCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCRISPR/Cas technologyCell LineCell physiologyCellsCellular biologyCessation of lifeChemicalsClinicalCritical PathwaysCytometryDataDiseaseElectronic Health RecordFrequenciesFutureGenesGeneticGenetic DatabasesGenetic PolymorphismGenetic Predisposition to DiseaseGenetic TranscriptionHereditary DiseaseHumanImmunityImmunologic Deficiency SyndromesImmunologicsImmunophenotypingImpairmentInfectionKnowledgeLearningLeftMalignant NeoplasmsMediatingMendelian disorderMethodsMolecular BiologyMusMutationMycobacterium InfectionsNatureNeutropeniaNonsense MutationPathway interactionsPatientsPeptide HydrolasesPersonsPopulation GeneticsPredispositionProteinsRare DiseasesResearchRiskRoleSTAT3 geneSamplingSerine ProteaseT cell differentiationT memory cellT-Cell ActivationT-LymphocyteTestingTherapeuticVariantWorkbiobankcell injurycongenital immunodeficiencyexome sequencingexperimental studyfollow-upgenetic approachgenetic disorder diagnosisgenetic varianthuman diseaseimmunoregulationinhibitorinterleukin-23memory CD4 T lymphocytemycobacterialneutrophilphenomepreventresponsereverse geneticssuicide inhibitor
项目摘要
PROJECT SUMMARY
Primary immunodeficiencies (PIDs) are a group of monogenic diseases caused by inborn errors of immunity
(IEI) that confer risk of severe infection, autoimmunity, and cancer. The genetic and immunological study of IEI
is instrumental to understand mechanisms of human immunity and to manage and treat patients with PIDs. Their
study is also important to understand more common diseases associated with genetic variants in the same
genes. However, despite the relevance and importance of studying PIDs from the basic science and clinical
points of view, half of the PID patients lack a genetic diagnosis. By studying a patient with a PID of unknown
genetic etiology that confers susceptibility to severe mycobacterial disease, we identified a nonsense mutation
in SERPINB1. Using a combination of population genetics, biochemistry, and molecular biology, we showed that
this is the first case of SERPINB1 complete deficiency ever described. SERPINB1 is an intracellular serine
protease suicide inhibitor. Its absence in mice causes uncontrolled intracellular protease activity, leading to
neutrophil death and subsequent neutropenia. Interestingly, our patient does not display any neutrophil
abnormality, but instead, our in-depth immunological characterization showed a reduction in the frequency of
activated T cells and CD4+ memory T cells. Our findings suggest that SERPINB1 has a previously unknown
function in T cells and antimycobacterial immunity. Our data also indicates that SERPINB1 orchestrates an
intracellular protease-mediated pathway essential for T cell activation and survival. Given our findings, this
application will test the hypothesis that SERPINB1 is critical for human T cell activation and, by controlling
intracellular protease activity, to human diseases. Capitalizing on the unique opportunity that this patient offers
to understand the function of human SERPINB1, we propose three complementary approaches. In Aim 1, we
will characterize the immunological consequences of SERPINB1 deficiency on T cell activation and CD4+ T cell
differentiation. We will also study the transcriptional consequences of SERPINB1 deficiency in T cells. With this,
we will uncover a previously unknown function of SERPINB1 in human T cells. In Aim 2, we will identify and
characterize the pathways orchestrated by SERPINB1 in T cells. The absence of SERPINB1 unleashes the
action of intracellular proteases. This rare mechanism of PID will allow for chemical inhibition of these proteases
for therapeutic purposes. Furthermore, characterizing the SERPINB1-dependent antimycobacterial mechanisms
will lead to the identification of additional IEI in its pathway in patients lacking a genetic diagnosis. In Aim 3, we
will perform phenome-wide association studies (pheWAS) to identify associations between genetic variants in
the SERPINB1 pathway and additional human diseases. This reverse genetic approach will expand what we will
learn from the study of a rare disease to benefit a broader group of patients. Our proposed research has far-
reaching clinical and biological implications for understanding SERPINB1 mediated immunity, PIDs, anti-
mycobacterial immunity, and the contribution of the SERPINB1 pathway to human disease.
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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Ruben Martinez Barricarte其他文献
Ruben Martinez Barricarte的其他文献
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- 批准号:
10629623 - 财政年份:2023
- 资助金额:
$ 66.5万 - 项目类别:
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$ 66.5万 - 项目类别:
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- 批准号:
10510731 - 财政年份:2022
- 资助金额:
$ 66.5万 - 项目类别:
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