Project 1: Understanding the molecular pathways in SLE pathogenesis
项目 1:了解 SLE 发病机制的分子途径
基本信息
- 批准号:9194911
- 负责人:
- 金额:$ 58.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-21 至 2017-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAntigen-Antibody ComplexAutoantibodiesAutoimmune DiseasesB-LymphocytesBiological AssayBiological MarkersBloodBlood CellsCellsChildhoodClinicalClinical TrialsClinical Trials DesignComplementDNADataDefectDendritic CellsDendritic cell activationDevelopmentDiagnosticDifferentiation AntigensDiseaseDisease remissionDisease susceptibilityFailureFlareGene ExpressionGene Expression ProfilingGenesGenomicsGoalsHereditary DiseaseHeterogeneityHumanImmune systemImmunityImmunophenotypingIn VitroIndividualInflammationInflammatoryInterferon Type IInterferonsLigandsLupusMeasuresMolecularMolecular ProfilingMyelogenousMyeloid CellsNatural ImmunityNuclear AntigensNucleic Acid BindingNucleic AcidsPathogenesisPathway interactionsPatientsPlasma CellsPlasmablastPopulationPrevalencePrincipal InvestigatorProductionResearchResourcesSamplingSourceStratificationSystemic Lupus ErythematosusTestingTherapeutic InterventionTranscriptTranscriptional ActivationVirginiaactivity markeradaptive immunityautoreactive B cellbiomarker developmentcell typecohortcomplement deficiencycomputerized toolscytokinegenetic signaturegenetic variantgenome wide association studyimmune activationin vitro Assayindividual patientmolecular markermolecular subtypesneutrophilpatient stratificationpersonalized therapeuticprogramsresponsesensortool
项目摘要
Program Director/Principal Investigator (Last, First, Middle): PD: Pascual, V. / PI: Project 1 Pascual, V.
Project Summary
Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by widespread inflammation
and development of autoantibodies against nuclear antigens. SLE is clinically heterogeneous and molecularly
diverse. This heterogeneity might contribute to the high occurrence of clinical trial failures, underscoring the
need for biomarkers to stratify patients according to individual pathogenic drivers of disease. In an attempt to
understand the complexity of SLE, we established a pediatric cohort and have followed it for the past decade
using validated clinical disease activity (DA) measures as well as blood gene expression profiles during flares
and remissions. Our studies confirm the prevalence of IFN, neutrophil/myeloid and plasmablast gene
signatures and their correlation with DA at the cohort level. Personalized immunomonitoring revealed,
however, significant heterogeneity in how these major signatures correlate with DA at the individual patient
level. We hypothesize that decoding the cellular and/or molecular components of these signatures in well-
defined groups of patients will enable development of biomarkers and computational tools for stratification,
which will enable rational clinical trial design.
Towards this goal, we are proposing two aims: 1) to establish the origin and composition of three major
SLE blood signatures at the single cell level. We will examine the cells that give rise to these signatures
using high definition immunophenotyping and transcriptional profiling at the population and single cell levels; 2)
to determine if molecular DA markers correlate with altered cytosolic and/or endosomal nucleic acid
(NA) sensing pathways in ex vivo patient blood cells and in vitro assays. Here, we first propose to apply
a sensitive and robust assay to quantify the endogenous activity of cGAS, a universal cytosolic DNA sensor, in
PBMCs from patients during flares and remissions. Second, we will test the response of patient cells to
relevant endosomal and cytosolic nucleic acid ligands in vitro using multi-dimensional readouts. Through the
implementation of our aims, we will i) reveal the source of SLE molecular signatures; ii) understand the extent
of heterogeneity of blood SLE myeloid cells and plasma cells; iii) determine which cell subsets/molecular
pathways and/or NA sensors contribute to immune activation leading to SLE flares. Understanding SLE
heterogeneity and developing tools to assess it in the clinical setting will ultimately open new paths towards
personalized therapeutic approaches.
项目主管/首席研究员(最后、第一、中):PD: Pascual, V. / PI: Project 1 Pascual, V.;
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Maria Virginia Pascual其他文献
Maria Virginia Pascual的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Maria Virginia Pascual', 18)}}的其他基金
Early life respiratory viral infections shape immune development trajectories
生命早期呼吸道病毒感染塑造免疫发育轨迹
- 批准号:
10435211 - 财政年份:2022
- 资助金额:
$ 58.2万 - 项目类别:
Early life respiratory viral infections shape immune development trajectories
生命早期呼吸道病毒感染塑造免疫发育轨迹
- 批准号:
10599202 - 财政年份:2022
- 资助金额:
$ 58.2万 - 项目类别:
Immune Cells and Secretory Pathways Leading to Human Systemic Autoimmunity
导致人类系统性自身免疫的免疫细胞和分泌途径
- 批准号:
10402544 - 财政年份:2021
- 资助金额:
$ 58.2万 - 项目类别:
Immune Cells and Secretory Pathways Leading to Human Systemic Autoimmunity
导致人类系统性自身免疫的免疫细胞和分泌途径
- 批准号:
10209399 - 财政年份:2020
- 资助金额:
$ 58.2万 - 项目类别:
Immune Cells and Secretory Pathways Leading to Human Systemic Autoimmunity
导致人类系统性自身免疫的免疫细胞和分泌途径
- 批准号:
10265722 - 财政年份:2020
- 资助金额:
$ 58.2万 - 项目类别:
Immune Cells and Secretory Pathways Leading to Human Systemic Autoimmunity
导致人类系统性自身免疫的免疫细胞和分泌途径
- 批准号:
9906169 - 财政年份:2019
- 资助金额:
$ 58.2万 - 项目类别:
相似海外基金
X-ray Structural Studies of Antigen-Antibody Complex Toward Malaria Vaccine Development.
用于疟疾疫苗开发的抗原抗体复合物的 X 射线结构研究。
- 批准号:
01044086 - 财政年份:1989
- 资助金额:
$ 58.2万 - 项目类别:
Grant-in-Aid for international Scientific Research