Biomarkers Of Beta Cell Stress In Type 1 Diabetes (BetaMarker)
1 型糖尿病 β 细胞应激的生物标志物 (BetaMarker)
基本信息
- 批准号:8813446
- 负责人:
- 金额:$ 240.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-23 至 2018-08-31
- 项目状态:已结题
- 来源:
- 关键词:AutoantibodiesAutoimmune ProcessBackBeta CellBioinformaticsBiological AssayBiological MarkersBiological PreservationBiologyC-PeptideCatalogingCatalogsCell DeathCell physiologyCellsCellular StressCessation of lifeClinicalClinical ResearchCytotoxic T-LymphocytesDNADevelopmentDiagnosisDiagnosticDiseaseEarly treatmentEnrollmentEvolutionFunctional disorderGenesGenomic IsletHealthHeterogeneityHumanImmuneImmune ToleranceIndividualInstitutionInsulinInsulin-Dependent Diabetes MellitusInterventionIslet CellMeasurementMediatingMetabolicMethylationNucleic AcidsOutcomePancreasPathogenesisPathway interactionsPharmaceutical PreparationsPlasmaPopulationPopulations at RiskPreventionProinsulinProteinsProteomicsRNA SplicingRecoveryResearchResourcesRiskSamplingScientistSequence AnalysisSerumSpecimenStagingStressTestingTimeTissuesTranscriptValidationassay developmentbasecohortdeep sequencingdiabetes riskdiabeticfunctional genomicshuman tissueimprovedinsulin secretionisletmacrophagenext generation sequencingnovelpreventpublic health relevancespectroscopic imagingstatistics
项目摘要
DESCRIPTION (provided by applicant): The pathogenesis of type 1 diabetes (T1D) involves islet beta cell loss mediated at a very late stage by cytotoxic T-cells and macrophages. Clinical studies have focused on the administration of immune modulatory drugs at the time of diagnosis, however, in none of these studies has the recovery or durable preservation of beta cell function been achieved. These disappointing outcomes have questioned both our understanding of the pathogenesis of the disease and whether timing of treatment (i.e. earlier in the disease) may yield better outcomes. An unmet need in the field has been the development of simple and reliable biomarkers that can identify those who have a virtually certain or very high
likelihood of developing T1D, thereby allowing for earlier treatment interventions. Recent studies from our research Team (Drs. Mirmira, Evans-Molina, Nadler, Metz, and Eizirik) and others suggest the provocative concept that stress pathways triggered within the beta cell very early in T1D evolution may initiate and/or accelerate autoimmune-mediated beta cell destruction. This overdue emphasis on the beta cell offers a unique opportunity to improve current T1D prediction strategies. This application is based on the hypothesis that stressed beta cells of pre-diabetic individuals liberate specific protein and DNA species into plasma, and that measurement of multiple such species can define the beta cell "stress signature" that confers risk for developing T1D. To test this hypothesis, we have assembled an interactive Team of scientists that will collectively engage its proteomics, functional genomics, islet biology, and bioinformatics/statistics expertise to identify protein and nucleic acid-derived biomarkers emanating from stressed beta cells that can stratify better the risk of developing T1D. This project, called "BetaMarker," will take a two-pronged approach: in the first, candidate beta cell-specific protein and nucleic acid biomarkers will be tested in human samples from the DPT-1 and TrialNet PTP cohorts, and in the second, a comprehensive proteomics and functional genomics approach will be undertaken to discover new beta cell-specific biomarkers that will be funneled back into testing in human populations. Three aims will be achieved: 1. Aim 1: Test candidate beta cell-derived protein biomarkers as predictors of T1D risk. 2. Aim 2: Validate differentially methylated DNA species as biomarkers of beta cell stress in T1D. 3. Aim 3: Identify novel protein and nucleic acid biomarkers of beta cell stress and T1D risk. The impact of the BetaMarker project will be the development of a group of biomarkers that reflect the beta cell "stress signature" and that will serve collectively or as components in a risk score for the development of T1D.
描述(申请人提供):1型糖尿病(T1D)的发病机制涉及胰岛β细胞在非常晚期由细胞毒性T细胞和巨噬细胞介导的丢失。临床研究的重点是在诊断时给予免疫调节药物,然而,在这些研究中,没有一项研究实现了β细胞功能的恢复或持久保存。这些令人失望的结果质疑了我们对疾病发病机制的理解,以及治疗的时机(即疾病早期)是否会产生更好的结果。该领域尚未得到满足的一个需求是开发简单可靠的生物标记物,可以识别那些几乎确定或非常高的
发生T1D的可能性,从而允许更早的治疗干预。我们的研究团队(Mirmira、Evans-Molina、Nadler、Metz和Eizirik博士)和其他人最近的研究表明,在T1D进化非常早的时候在β细胞内触发的应激通路可能启动和/或加速自身免疫介导的β细胞破坏。这种迟来的对β细胞的重视为改进当前的T1D预测策略提供了一个独特的机会。这一应用是基于这样的假设,即糖尿病前期患者的应激β细胞将特定的蛋白质和DNA释放到血浆中,并且对多个这样的物种的测量可以定义导致T1D风险的贝塔细胞“应激信号”。为了验证这一假设,我们组建了一个互动的科学家团队,他们将共同参与其蛋白质组学、功能基因组学、胰岛生物学和生物信息学/统计学专业知识,以确定源自应激的β细胞的蛋白质和核酸衍生生物标记物,这些生物标记物可以更好地对发生T1D的风险进行分层。这项名为“BetaMarker”的项目将采取双管齐下的方法:第一,将在DPT-1和TrialNet PTP队列的人类样本中测试候选的Beta细胞特异性蛋白质和核酸生物标志物;第二,将采用全面的蛋白质组学和功能基因组学方法,发现新的Beta细胞特异性生物标志物,这些生物标志物将在人类群体中进行测试。将实现三个目标:1.目标1:测试候选的β细胞衍生蛋白生物标记物作为T1D风险的预测因子。2.目的2:验证差异甲基化DNA作为T1D时β细胞应激的生物标志物。3.目的3:寻找新的β细胞应激和T1D风险的蛋白质和核酸生物标志物。BetaMarker项目的影响将是开发一组生物标记物,这些生物标记物反映贝塔细胞的“压力信号”,并将共同或作为T1D发展风险评分的组成部分。
项目成果
期刊论文数量(22)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
ER stress and the decline and fall of pancreatic beta cells in type 1 diabetes.
- DOI:10.3109/03009734.2015.1135217
- 发表时间:2016-05
- 期刊:
- 影响因子:3.4
- 作者:Brozzi F;Eizirik DL
- 通讯作者:Eizirik DL
Checks and Balances-The Limits of β-Cell Endurance to ER Stress.
检查与平衡-β细胞对内质网应激的耐受力的极限。
- DOI:10.2337/dbi17-0018
- 发表时间:2017
- 期刊:
- 影响因子:7.7
- 作者:Eizirik,DecioL;CoomansdeBrachène,Alexandra
- 通讯作者:CoomansdeBrachène,Alexandra
MicroRNAs miR-23a-3p, miR-23b-3p, and miR-149-5p Regulate the Expression of Proapoptotic BH3-Only Proteins DP5 and PUMA in Human Pancreatic β-Cells.
- DOI:10.2337/db16-0592
- 发表时间:2017-01
- 期刊:
- 影响因子:7.7
- 作者:Grieco FA;Sebastiani G;Juan-Mateu J;Villate O;Marroqui L;Ladrière L;Tugay K;Regazzi R;Bugliani M;Marchetti P;Dotta F;Eizirik DL
- 通讯作者:Eizirik DL
MECHANISMS IN ENDOCRINOLOGY: Alternative splicing: the new frontier in diabetes research.
- DOI:10.1530/eje-15-0916
- 发表时间:2016-05
- 期刊:
- 影响因子:5.8
- 作者:Juan-Mateu J;Villate O;Eizirik DL
- 通讯作者:Eizirik DL
Precision medicine in type 1 diabetes.
- DOI:10.1007/s00125-022-05778-3
- 发表时间:2022-11
- 期刊:
- 影响因子:8.2
- 作者:Carr, Alice L. J.;Evans-Molina, Carmella;Oram, Richard A.
- 通讯作者:Oram, Richard A.
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Decio laks Eizirik其他文献
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{{ truncateString('Decio laks Eizirik', 18)}}的其他基金
Implications of Changes in Islet Exosomal Cargo in Type 1 Diabetes
1 型糖尿病中胰岛外泌体货物变化的影响
- 批准号:
10708900 - 财政年份:2022
- 资助金额:
$ 240.17万 - 项目类别:
The Integrated Stress Response in Human Islets During Early T1D
早期 T1D 期间人体胰岛的综合应激反应
- 批准号:
10440523 - 财政年份:2020
- 资助金额:
$ 240.17万 - 项目类别:
The Integrated Stress Response in Human Islets During Early T1D
早期 T1D 期间人体胰岛的综合应激反应
- 批准号:
10262963 - 财政年份:2020
- 资助金额:
$ 240.17万 - 项目类别:
The Integrated Stress Response in Human Islets During Early T1D
早期 T1D 期间人体胰岛的综合应激反应
- 批准号:
10653122 - 财政年份:2020
- 资助金额:
$ 240.17万 - 项目类别: