Somatic Mutation in the Etiology of Multiple Sclerosis
Somatic Mutation in the Etiology of Multiple Sclerosis
批准号:
9180380
负责人:
RICHARD H SCHEUERMANN
金额:
$35.67万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-07-01 至 2018-06-30
关键词:
AddressAdvanced DevelopmentAffectAntibodiesAntigen ReceptorsApoptoticAreaAutoantigensAutoimmune DiseasesAutoimmune ResponsesAutoimmunityB-LymphocytesBioinformaticsBlood CellsBrainCRISPR/Cas technologyCell LineCellsCerebrospinal FluidCharacteristicsChronicClinicalComplex MixturesConstitutionalDNA Sequence AlterationDataDefectDemyelinationsDevelopmentDiseaseDisease ProgressionEpigenetic ProcessEtiologyEventExhibitsFamilyGene TargetingGenesGenetic Predisposition to DiseaseGenomeGenomicsGoalsHumanIL4 geneImmune ToleranceImmune responseImmune systemIndividualInflammatoryInheritedLesionLymphocyteMalignant NeoplasmsMemory B-LymphocyteMessenger RNAMethodologyMethodsMolecularMolecular ProfilingMultiple SclerosisMutateMutationNeuraxisNormal CellOnset of illnessParticipantPathologyPatternPhysiologicalPlayQuality ControlRegulationRelapsing-Remitting Multiple SclerosisResearchRiskRoleSequence AnalysisSignal PathwaySignal TransductionSomatic MutationStochastic ProcessesT-LymphocyteTNFRSF5 geneTestingTissue-Specific Gene ExpressionTissuesTumor Suppressor Genesalternative treatmentautoreactive B cellbasecomparativedifferential expressiondisorder riskexperiencegenome-widehigh riskhuman diseaseimprovedmacrophagemultiple sclerosis patientpersonalized medicinereceptorresponsetranscriptometranscriptome sequencingtranscriptomicswhole genome
中文摘要
项目总结
英文摘要
Project Summary
Autoimmune diseases are a family of over 80 chronic, disabling illnesses in which defects in the immune
system leads the body to attack normal components (self antigens) of its own tissues. Autoimmune disease
affects 14.7 – 23.5 million people in the U.S. alone (5 – 8%), making it one of the most common classes of
human diseases. However, despite considerable research being devoted to understanding autoimmunity, a
coherent explanation of the critical causative events that initiate the autoimmune response is still lacking.
Familial clustering of autoimmune disease indicates that an increased risk of disease, a genetic predisposition,
can be inherited. But even in settings in which risk is inherited, disease onset is found to occur after a variable
delay, suggesting that additional stochastic processes are necessary to trigger disease onset. This
phenomenon is reminiscent of what has been observed in cancer where a genetic predisposition can be
inherited, and yet cancer develops only after somatic mutations in additional target genes occur. Thus, the
goal of the project described in this proposal is to test the hypothesis that somatic mutations in genes that
regulate immune tolerance are required to initiate autoimmunity, by performing single cell RNA-seq-based
expression profiling and sequence analysis of pathogenic lymphocytes from multiple sclerosis (MS) patients.
Although the inflammatory lesions found in the central nervous system (CNS) of MS patients include a complex
mixture of T cells, B cells and macrophages, the presence of clonally-expanded, receptor-edited and
somatically-mutated memory B cells that express brain-reactive antibodies in the cerebrospinal fluid (CSF),
and the dramatic clinical response to B cell depletion therapy, suggest that autoreactive B cells play a critical
role in MS pathology, and are therefore the focus of the proposed studies.
Three specific aims are proposed: 1. Determine if pathogenic B cells in the CSF of MS patients carry somatic
mutations in genes involved in regulating B cell tolerance, 2. Determine if pathogenic B cells in the CSF of MS
patients exhibit altered transcriptional profiles either constitutively or in response to activating signals, and 3.
Investigate the functional relevance of somatic mutations detected on tolerance-related signaling pathways.
Through the genome-wide comparative analysis of mRNA sequence and expression data of single CSF B cells
from MS patients we expect to determine if somatic mutations and their effects can be identified in pathogenic
cells. We will also have developed a validated single cell RNA-seq methodology for the conduct of similar
studies in other autoimmune disease and immune response settings. The development of advanced single
cell genomic methodologies that will allow us to explore the potential role of somatic mutations and differential
gene expression in the etiology of MS will be a real game changer. Evidence for a role for somatic mutations
in MS etiology and/or pathology would completely change the way we view autoimmune disease development
and would have broad implications for the development of alternative personalized treatment approaches.
OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page
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Bioinformatics Resource Center
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批准号:8147328
-
项目类别:
-
资助金额:$6.09万
-
财政年份:2009
-
负责人:RICHARD H SCHEUERMANN
-
依托单位:
Bioinformatics Resource Center
-
批准号:8693850
-
项目类别:
-
资助金额:$430.83万
-
财政年份:2009
-
负责人:RICHARD H SCHEUERMANN
-
依托单位:--
Bioinformatics Resource Center
-
批准号:8867924
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项目类别:
-
资助金额:$0.63万
-
财政年份:2009
-
负责人:RICHARD H SCHEUERMANN
-
依托单位:--
Bioinformatics Resource Center
-
批准号:8147336
-
项目类别:
-
资助金额:$115.66万
-
财政年份:2009
-
负责人:RICHARD H SCHEUERMANN
-
依托单位:
Bioinformatics Resource Center
-
批准号:8513846
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项目类别:
-
资助金额:$65.59万
-
财政年份:2009
-
负责人:RICHARD H SCHEUERMANN
-
依托单位:
Bioinformatics Resource Centers
-
批准号:8513847
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项目类别:
-
资助金额:$65.59万
-
财政年份:2009
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负责人:RICHARD H SCHEUERMANN
-
依托单位:
BISC PHASE II
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批准号:7543645
-
项目类别:
-
资助金额:$740.93万
-
财政年份:2004
-
负责人:RICHARD H SCHEUERMANN
-
依托单位:--
Bioinformatics Integration Support Contract for Biodefense
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批准号:7891935
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项目类别:
-
资助金额:$689.93万
-
财政年份:2004
-
负责人:RICHARD H SCHEUERMANN
-
依托单位:
Bioinformatics Integration Support Contract for Biodefense
-
批准号:8151533
-
项目类别:
-
资助金额:$339.95万
-
财政年份:2004
-
负责人:RICHARD H SCHEUERMANN
-
依托单位:
BIOINFORMATICS RESOURCE CENTERS FOR BIODEFENSE
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批准号:7543671
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项目类别:
-
资助金额:$342.64万
-
财政年份:2004
-
负责人:RICHARD H SCHEUERMANN
-
依托单位:--
BIOINFORMATICS RESOURCE CENTERS
-
批准号:7923430
-
项目类别:
-
资助金额:$1678.25万
-
财政年份:2004
-
负责人:RICHARD H SCHEUERMANN
-
依托单位:
BIOINFORMATICS RESOURCE CENTERS
-
批准号:8135843
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项目类别:
-
资助金额:$63.66万
-
财政年份:2004
-
负责人:RICHARD H SCHEUERMANN
-
依托单位:
Functional Characterization of BAFF-induced Genes
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批准号:6841176
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项目类别:
-
资助金额:$39.0万
-
财政年份:2003
-
负责人:RICHARD H SCHEUERMANN
-
依托单位:
Functional Characterization of BAFF-induced Genes
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批准号:6999780
-
项目类别:
-
资助金额:$38.08万
-
财政年份:2003
-
负责人:RICHARD H SCHEUERMANN
-
依托单位:
Functional Characterization of BAFF-induced Genes
-
批准号:7177536
-
项目类别:
-
资助金额:$36.98万
-
财政年份:2003
-
负责人:RICHARD H SCHEUERMANN
-
依托单位:
Functional Characterization of BAFF-induced Genes
-
批准号:6677221
-
项目类别:
-
资助金额:$19.5万
-
财政年份:2003
-
负责人:RICHARD H SCHEUERMANN
-
依托单位:
Functional Characterization of BAFF-induced Genes
-
批准号:6760112
-
项目类别:
-
资助金额:$39.0万
-
财政年份:2003
-
负责人:RICHARD H SCHEUERMANN
-
依托单位:
Database development and modeling of signal transduction
-
批准号:6445433
-
项目类别:
-
资助金额:$1.9万
-
财政年份:2002
-
负责人:RICHARD H SCHEUERMANN
-
依托单位:
POPULATION STABILITY IN TUMOR DORMANCY
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批准号:2896642
-
项目类别:
-
资助金额:$24.25万
-
财政年份:1998
-
负责人:RICHARD H SCHEUERMANN
-
依托单位:
POPULATION STABILITY IN TUMOR DORMANCY
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批准号:6377200
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项目类别:
-
资助金额:$25.47万
-
财政年份:1998
-
负责人:RICHARD H SCHEUERMANN
-
依托单位:
海外基金