Characterization of beta-cell-specific extracellular vesicle cargo as functional biomarkers for type I DM disease
β细胞特异性细胞外囊泡货物作为 I 型 DM 疾病功能性生物标志物的表征
基本信息
- 批准号:10706576
- 负责人:
- 金额:$ 75.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-19 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAutoantigensAutocrine CommunicationAutoimmuneAutoimmune DiseasesAutoimmunityB-LymphocytesBeta CellBioinformaticsBiological MarkersBiological ModelsBiologyBloodBone MarrowCase/Control StudiesCell LineCell physiologyCellsCellular biologyCharacteristicsChildChildhoodCirculationClinicalCommunicationCommunitiesDataData SetDetectionDevelopmentDiabetes MellitusDiscriminationDiseaseEarly DiagnosisEventFundingGenetic TranscriptionGoalsHealthHistologyHumanHuman Cell LineImmuneImmune responseImmune systemImmunologicsIn VitroIndividualInflammationInflammatoryInjuryInsulinInsulin-Dependent Diabetes MellitusIslet CellIslets of LangerhansLaboratoriesMacrophageMeasuresMediatingMediatorMembraneMembrane PotentialsMembrane ProteinsMetabolic DiseasesMetabolismMethodsMitochondriaModelingMolecularMorbidity - disease rateMusNational Institute of Diabetes and Digestive and Kidney DiseasesNatural ImmunityOxidative StressPancreasPancreatic InjuryPathogenesisPathologicPatientsPeripheralPersonsPhasePhenotypePlasmaPopulationPredispositionProcessProductionProteinsProteomicsRNARNA DatabasesReporterResearchRiskRoleSentinelSignal TransductionSpecificityStimulusStressStructure of beta Cell of isletSynapsesSystemTechniquesTissuesTranscriptTranslationsUnited States National Institutes of Healthcell injurycohortcytokinediabetes pathogenesisdisease diagnosticearly detection biomarkersextracellular vesiclesglucose uptakehuman tissueimmune activationimmunoregulationin vivoinsightinsulin dependent diabetes mellitus onsetintercellular communicationisletlipid metabolismmonocytemortalityneutrophilnovelperipheral bloodpre-clinicalpreventprotein biomarkersresponsesingle nucleus RNA-sequencingtraffickingtranscriptome sequencingtranslational study
项目摘要
1 Type 1 diabetes (T1D) is an autoimmune disease afflicting nearly 2 million people in the U.S. The loss of insulin-
2 producing β cells in the pancreas results in an absolute requirement for injected insulin, causing significant risks
3 of mortality and morbidity. T1D is characterized by a latent (asymptomatic) phase, during which autoimmune or
4 inflammatory pancreatic beta cell injury is postulated to lead to a decline in beta cell function/mass and ultimately
5 to T1D. A key goal in T1D is halting the autoimmune cellular attack, by limiting immune-mediated damage. The
6 precise intrapancreatic signaling mechanisms that lead to activation of the immune system and early pancreatic
7 injury remain unclear. Identification of markers closely associated with these key immune events in the
8 pathogenesis of T1D that can be detected in peripheral circulation would allow for detection of pre-clinical
9 disease and tracking of disease trajectory. Extracellular vesicles (EVs) and their contents have emerged as novel
10 mediators of intercellular signaling and functional biomarkers in human metabolic diseases. Data from our
11 collaborative group as part of NIH efforts in EV biology (NIH Common Fund) suggest that circulating cell-specific
12 EVs and their cargo as probes for disease trajectory or cellular health provide greater specificity than traditional
13 circulating RNA or protein biomarkers in whole plasma. Recent studies in T1D suggest that pancreatic beta cells
14 under “stress” produce EVs containing auto-antigens and RNA transcripts that may mediate communication
15 between pancreatic and immune cells by transfer of molecular cargo. Nevertheless, studies characterizing the
16 functional landscape of pancreatic beta-cell-derived EVs in T1D, and their implications as biomarkers of T1D
17 susceptibility in childhood, are lacking. In response to RFA-DK-21-016, we hypothesize that pancreatic islet cell-
18 derived EVs are functional reporters of islet cell biology and contain RNA cargo relevant to regulation of immune
19 responses and beta cell health early in T1D. In Aim 1, we utilize well-established human cellular systems of
20 pancreatic injury (human cell-line and donated human islets, with and without cytokine-mediated injury)
21 alongside methods established by our group to provide proteomic and transcriptional characterization of beta-
22 cell-derived EVs, with isolation of pancreatic beta-cell specific EVs from human circulation in children with and
23 without T1D. In Aim 2, we define the functional role for pancreatic beta-cell specific EVs in innate immune
24 function (macrophages, neutrophils) postulated to serve as early mediators of pancreatic injury via assessments
25 of immunometabolic phenotypes and responses to in vivo administration of human EVs to a diabetes-prone
26 model system. In Aim 3, we will use RNA-seq and bioinformatics to identify pancreatic beta cell-specific
27 transcripts associated with incident T1D from children from the long-standing NIDDK TEDDY study (n=140, 1:1
28 T1D case/control) at high immunologic risk for T1D. Upon completion, this application will provide a broad
29 phenotypic, functional and clinical characterization of human beta cell derived EVs toward developing a signature
30 of pancreatic cell-specific EVs relevant to early T1D development, addressing the aims of RFA-DK-21-016.
1型糖尿病(T1D)是一种自身免疫性疾病,在美国有近200万人患有此病
项目成果
期刊论文数量(0)
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Saumya Das其他文献
Saumya Das的其他文献
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{{ truncateString('Saumya Das', 18)}}的其他基金
Characterization of beta-cell-specific extracellular vesicle cargo as functional biomarkers for type I DM disease
β细胞特异性细胞外囊泡货物作为 I 型 DM 疾病功能性生物标志物的表征
- 批准号:
10517890 - 财政年份:2022
- 资助金额:
$ 75.37万 - 项目类别:
Using ex vivo, in vivo models and patient mutations to interrogate pancreatic exocrine-endocrine cross talk
使用离体、体内模型和患者突变来探究胰腺外分泌-内分泌串扰
- 批准号:
10706558 - 财政年份:2022
- 资助金额:
$ 75.37万 - 项目类别:
Using ex vivo, in vivo models and patient mutations to interrogate pancreatic exocrine-endocrine cross talk
使用离体、体内模型和患者突变来探究胰腺外分泌-内分泌串扰
- 批准号:
10594228 - 财政年份:2022
- 资助金额:
$ 75.37万 - 项目类别:
Functional role and therapeutic targeting of exosomes and extracellular RNA biomarkers in heart failure
外泌体和细胞外 RNA 生物标志物在心力衰竭中的功能作用和治疗靶向
- 批准号:
9894484 - 财政年份:2020
- 资助金额:
$ 75.37万 - 项目类别:
Functional role and therapeutic targeting of exosomes and extracellular RNA biomarkers in heart failure
外泌体和细胞外 RNA 生物标志物在心力衰竭中的功能作用和治疗靶向
- 批准号:
10417068 - 财政年份:2020
- 资助金额:
$ 75.37万 - 项目类别:
Functional role and therapeutic targeting of exosomes and extracellular RNA biomarkers in heart failure
外泌体和细胞外 RNA 生物标志物在心力衰竭中的功能作用和治疗靶向
- 批准号:
10176560 - 财政年份:2020
- 资助金额:
$ 75.37万 - 项目类别:
Functional role and therapeutic targeting of exosomes and extracellular RNA biomarkers in heart failure
外泌体和细胞外 RNA 生物标志物在心力衰竭中的功能作用和治疗靶向
- 批准号:
10630193 - 财政年份:2020
- 资助金额:
$ 75.37万 - 项目类别:
Molecular dissection and imaging of extracellular vesicles to define their origin and targets
细胞外囊泡的分子解剖和成像以确定其起源和目标
- 批准号:
9811730 - 财政年份:2019
- 资助金额:
$ 75.37万 - 项目类别:
Molecular dissection and imaging of extracellular vesicles to define their origin and targets
细胞外囊泡的分子解剖和成像以确定其起源和目标
- 批准号:
10350010 - 财政年份:2019
- 资助金额:
$ 75.37万 - 项目类别:
Molecular dissection and imaging of extracellular vesicles to define their origin and targets
细胞外囊泡的分子解剖和成像以确定其起源和目标
- 批准号:
10018945 - 财政年份:2019
- 资助金额:
$ 75.37万 - 项目类别:
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