Characterizing the serum metabolome in multiple sclerosis
描述多发性硬化症的血清代谢组特征
基本信息
- 批准号:10390352
- 负责人:
- 金额:$ 60.37万
- 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:2021-04-15 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AntibodiesAntigen PresentationAutoimmune DiseasesBindingBiochemicalBiologicalBiological MarkersBiological ProcessChronicClassificationClinicComplementDemyelinating DiseasesDevelopmentDiagnosisDiagnosticDiagnostic SensitivityDiagnostic SpecificityDiscriminationDiseaseDisease remissionEarly treatmentEvaluationFDA approvedFinancial costFree WillGenesGeneticGoalsGuidelinesHLA-DRB1HealthInflammatoryMedical Care CostsMetabolicMetabolite InteractionMigraineModelingMolecularMonitorMultiple SclerosisNerve DegenerationNeuraxisNeurologic SymptomsNeuromyelitis OpticaOutcomePatientsPatternPeptidesPersonsPharmaceutical PreparationsPhaseProcessPrognostic MarkerRelapseResearchResourcesRiskRisk FactorsSamplingSerumSerum MarkersSignal TransductionSjogren&aposs SyndromeSpecificitySuggestionSupervisionSystemic Lupus ErythematosusTestingTimeTreatment outcomeVariantautoreactive T cellclinical diagnosiscohortcostdiagnostic biomarkerdisabilitydisorder controlimmunomodulatory therapiesimprovedimproved outcomemachine learning classificationmedical specialtiesmetabolomemetabolomicsmultiple sclerosis patientmultiple sclerosis treatmentnovelnovel therapeuticsoligodendrocyte-myelin glycoproteinside effectsupervised learningtargeted therapy trialstrait
项目摘要
PROJECT SUMMARY AND ABSTRACT
Within the last decade, we have made great strides in our understanding of the mechanisms underlying
multiple sclerosis (MS) risk and progression, however much of the variation remains unexplained. We have
achieved significant reductions in the time to diagnosis and we have improved diagnostic sensitivity, however
specificity is not ideal. Further, most of the FDA-approved MS-specific immunomodulatory therapies (IMTs) focus
on the inflammatory disease component in the relapsing phase and have little effect on improving outcomes
once a patient enters the progressive phase. The challenge for drug trials is the lack biomarkers to detect and
monitor MS progression. The objectives of the current application are: 1. To identify and characterize
biomarkers that discriminate MS and from other central nervous system inflammatory demyelinating diseases
(CNSIDDs) and non-CNSIDD controls, and 2. To identify biomarkers of disease activity and biomarkers that
distinguish relapsing from progressive forms of MS. We propose a multi-stage analysis of pre-existing and well-
defined biological samples from two resources.
Aim 1. Identify biochemical traits that discriminate MS from other CNSIDDs and healthy controls.
Supervised machine learning and classification models will identify a metabolic signature discriminating MS from
other CNSIDDs and healthy controls (HCs) in two cohorts. In the 1st cohort, MS patients who are early in their
diagnosis (≤ 2 years) and IMT naïve/free will be compared to HCs and other CNSIDD cases. Discriminating
metabolites will be tested for replication in a 2nd cohort comparing similarly defined MS patients to HCs and other
CNSIDDs, and other autoimmune disease patients. We will determine the direction of the replicating MS-
metabolite associations using bidirectional genetic instrumental variable analyses. Aim 2. Identify biochemical
features of MS disease activity. We will identify metabolic variation corresponding to disease activity by
comparing IMT naïve/free patients within 2 years of diagnosis and with a recent relapse to those who have been
in remission for ≥3 months and to HCs using supervised classification in a discovery cohort followed by
replication analyses in a 2nd cohort. Aim 3. Identify biochemical traits that discriminate progressive from
relapsing MS. Supervised machine learning and classification models will identify metabolic patterns associated
with MS progression by comparing IMT naïve/free patients with relapsing forms of MS to progressive MS from
at a single academic specialty clinic. Aim 4. Identify metabolites that interact with HLA-DRB1*15:01 to
increase MS risk. In this exploratory aim we will identify gene-metabolite (GxM) interactions involving the
primary MS risk factor, HLA-DRB1*15:01. The encoded peptide is involved in antigen presentation and
effectively binds to many endogenous metabolites, suggesting a mechanism through which autoreactive T cells
may be activated. We will conduct GxM analyses in MS-HC matched pairs to identify metabolites associated
with MS risk in the context of HLA-DRB1.
At the completion of the proposed research, our expected outcomes are to have identified and
characterized a serum-derived metabolomic signature that discriminates MS from other CNSIDDs and non-
CNSIDD controls. We also expect to have identified novel serum markers of MS disease activity and
progression, as well as putative metabolites that interact with HLA-DRB1*15:01 to modify risk. These results will
have an important positive impact by identifying serum-derived biochemical traits that could be used to improve
diagnostic specificity in MS. There is also the promise of discerning novel molecular processes underlying MS,
which will provide new opportunities for the development and evaluation of novel therapies.
项目总结与摘要
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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Farren B. S. Briggs其他文献
Mind the gap: resources required to receive, process and interpret research-returned whole genome data
- DOI:
10.1007/s00439-019-02033-5 - 发表时间:
2019-06-03 - 期刊:
- 影响因子:3.600
- 作者:
Dana C. Crawford;Jessica N. Cooke Bailey;Farren B. S. Briggs - 通讯作者:
Farren B. S. Briggs
Exploring the early drivers of pain in Parkinson’s disease
- DOI:
10.1038/s41598-025-90678-w - 发表时间:
2025-02-20 - 期刊:
- 影响因子:3.900
- 作者:
Shiying Liu;Douglas D. Gunzler;Steven A. Gunzler;Dana C. Crawford;Farren B. S. Briggs - 通讯作者:
Farren B. S. Briggs
Male sexual and reproductive health in multiple sclerosis: a scoping review
- DOI:
10.1007/s00415-024-12250-2 - 发表时间:
2024-02-28 - 期刊:
- 影响因子:4.600
- 作者:
Karlo Toljan;Farren B. S. Briggs - 通讯作者:
Farren B. S. Briggs
Farren B. S. Briggs的其他文献
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{{ truncateString('Farren B. S. Briggs', 18)}}的其他基金
Elucidating symptoms clusters in multiple sclerosis using patient reported outcomes and unsupervised machine learning
使用患者报告的结果和无监督的机器学习来阐明多发性硬化症的症状群
- 批准号:
10440701 - 财政年份:2021
- 资助金额:
$ 60.37万 - 项目类别:
Characterizing the serum metabolome in multiple sclerosis
描述多发性硬化症的血清代谢组特征
- 批准号:
10197636 - 财政年份:2021
- 资助金额:
$ 60.37万 - 项目类别:
Elucidating symptoms clusters in multiple sclerosis using patient reported outcomes and unsupervised machine learning
使用患者报告的结果和无监督的机器学习来阐明多发性硬化症的症状群
- 批准号:
10474610 - 财政年份:2021
- 资助金额:
$ 60.37万 - 项目类别:
Characterizing the serum metabolome in multiple sclerosis
描述多发性硬化症的血清代谢组特征
- 批准号:
10597006 - 财政年份:2021
- 资助金额:
$ 60.37万 - 项目类别:
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