Beta-cell responses to oxidative stress and Type 1 diabetes
β 细胞对氧化应激和 1 型糖尿病的反应
基本信息
- 批准号:10406857
- 负责人:
- 金额:$ 63.51万
- 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:2021-07-01 至 2022-12-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAddressAftercareAntioxidantsAntiviral ResponseAttenuatedAutoimmune DiseasesAutoimmunityB-LymphocytesBeta CellCell MaintenanceCell physiologyCellsCharacteristicsChronicDataDiabetes MellitusDrug ModelingsEtiologyExhibitsFunctional disorderFutureGene ExpressionGene Expression ProfileGenerationsGenesGeneticHumanImmuneIn VitroInbred NOD MiceInflammatory ResponseInsulinInsulin-Dependent Diabetes MellitusInterferon Type ILeukocytesLinkManganeseMediatingMessenger RNAMetalloporphyrinsModelingMusNADPH OxidaseNon obeseOnset of illnessOxidative StressParticipantPharmaceutical PreparationsPharmacologyPhenotypeProteinsReactive Oxygen SpeciesResearchResistanceRoleStructure of beta Cell of isletSuperoxidesTestingTherapeuticTissuesblood glucose regulationchemokinecomparativecytokinediabetes pathogenesisdiabeticeffector T cellexperimental studyin vivoinflammatory milieuinsightinsulin secretionisletmouse modelpreservationprotein biomarkersresponse
项目摘要
Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic β-cell destruction due to the generation of reactive oxygen species (ROS), proinflammatory cytokines/chemokines, and T cell effector molecules. Recent evidence has shown that β-cell dysfunction is also an activate participant in T1D pathogenesis. We will compare pancreatic β-cell functional identity changes that occur with T1D-prone Non-obese Diabetic (NOD) mice with T1D-resistant NOD.Ncf1m1J mice unable to generate NADPH oxidase (NOX)-derived superoxide. We will examine how the absence of ROS in NOD.Ncf1m1J mice can regulate β-cell functional identity, interactions with immune cells, and delay in T1D. To corroborate our genetic mouse models, we will examine pancreatic β-cell responses following treatment with a pharmacological manganese metalloporphyrin antioxidant with human islets. Our overarching hypothesis is that ROS reduction will preserve or enhance β-cell functional identity, as defined by transcriptional signatures and insulin secretion in T1D-prone NOD mice and human islets. To address this hypothesis, the following independent and interrelated aims will be defined: (1) Define how genetic ablation of ROS preserves β-cell functional identity. (2) Determine whether the absence of ROS can decrease pancreatic β-cell-mediated inflammatory responses. (3) Determine whether antioxidant treatment preserves the function of mouse and human β-cells. The insights gained from our studies will increase our understanding of diabetes etiology and may also point to future strategies employing antioxidant compounds to preserve and/or replace the function of pancreatic β-cells.
1 型糖尿病 (T1D) 是一种自身免疫性疾病,由于活性氧 (ROS)、促炎细胞因子/趋化因子和 T 细胞效应分子的产生而导致胰腺 β 细胞破坏。最近的证据表明,β 细胞功能障碍也是 T1D 发病机制的活跃参与者。我们将比较易患 T1D 的非肥胖糖尿病 (NOD) 小鼠和抗 T1D NOD.Ncf1m1J 小鼠发生的胰腺 β 细胞功能特性变化。Ncf1m1J 小鼠无法产生 NADPH 氧化酶 (NOX) 衍生的超氧化物。我们将研究 NOD.Ncf1m1J 小鼠中 ROS 的缺失如何调节 β 细胞功能特性、与免疫细胞的相互作用以及延迟 T1D。为了证实我们的基因小鼠模型,我们将检查用药理学锰金属卟啉抗氧化剂和人胰岛治疗后胰腺 β 细胞的反应。我们的总体假设是,ROS 减少将保留或增强 β 细胞功能特性,如易患 T1D 的 NOD 小鼠和人类胰岛的转录特征和胰岛素分泌所定义的那样。为了解决这一假设,将定义以下独立且相互关联的目标:(1)定义 ROS 的遗传消融如何保留 β 细胞功能特性。 (2)确定ROS的缺失是否可以降低胰腺β细胞介导的炎症反应。 (3) 确定抗氧化治疗是否能保留小鼠和人类β细胞的功能。从我们的研究中获得的见解将增加我们对糖尿病病因学的理解,并且还可能指出未来使用抗氧化剂化合物来保护和/或替代胰腺β细胞功能的策略。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Chad S Hunter其他文献
Chad S Hunter的其他文献
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{{ truncateString('Chad S Hunter', 18)}}的其他基金
Beta-cell responses to oxidative stress and Type 1 diabetes
β 细胞对氧化应激和 1 型糖尿病的反应
- 批准号:
10154970 - 财政年份:2021
- 资助金额:
$ 63.51万 - 项目类别:
A novel link between gene regulation and histone modifications governing islet beta-cell development and function
基因调控与控制胰岛β细胞发育和功能的组蛋白修饰之间的新联系
- 批准号:
10365325 - 财政年份:2021
- 资助金额:
$ 63.51万 - 项目类别:
Beta-cell responses to oxidative stress and Type 1 diabetes
β 细胞对氧化应激和 1 型糖尿病的反应
- 批准号:
10610957 - 财政年份:2021
- 资助金额:
$ 63.51万 - 项目类别:
A novel link between gene regulation and histone modifications governing islet beta-cell development and function
基因调控与控制胰岛β细胞发育和功能的组蛋白修饰之间的新联系
- 批准号:
10532763 - 财政年份:2021
- 资助金额:
$ 63.51万 - 项目类别:
Beta-cell responses to oxidative stress and Type 1 diabetes
β 细胞对氧化应激和 1 型糖尿病的反应
- 批准号:
10161013 - 财政年份:2020
- 资助金额:
$ 63.51万 - 项目类别:
Revealing LIM Domain Transcriptional Complexes that establish and maintain Beta Cell Mass
揭示建立和维持 β 细胞质量的 LIM 结构域转录复合物
- 批准号:
9922287 - 财政年份:2017
- 资助金额:
$ 63.51万 - 项目类别:
Revealing LIM Domain Transcriptional Complexes that establish and maintain Beta Cell Mass
揭示建立和维持 β 细胞质量的 LIM 结构域转录复合物
- 批准号:
10161764 - 财政年份:2017
- 资助金额:
$ 63.51万 - 项目类别:
Ldb1-mediated transcriptional complexes during beta-cell development and function
β 细胞发育和功能过程中 Ldb1 介导的转录复合物
- 批准号:
9110565 - 财政年份:2016
- 资助金额:
$ 63.51万 - 项目类别:
The Ldb1 coregulator controls LIM target genes in developing and adult islets.
Ldb1 核心调节器控制发育中和成年胰岛中的 LIM 靶基因。
- 批准号:
8846104 - 财政年份:2013
- 资助金额:
$ 63.51万 - 项目类别:
The Ldb1 coregulator controls LIM target genes in developing and adult islets.
Ldb1 核心调节器控制发育中和成年胰岛中的 LIM 靶基因。
- 批准号:
8441317 - 财政年份:2013
- 资助金额:
$ 63.51万 - 项目类别:
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