Dextran Sulfate, Beta Cell Preservation and Immune Regulation in Type 1 Diabetes
硫酸葡聚糖、β 细胞保存和 1 型糖尿病的免疫调节
基本信息
- 批准号:9289335
- 负责人:
- 金额:$ 42.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-04-01 至 2021-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAntigen-Presenting CellsAntigensAutoimmunityB-LymphocytesBacterial PolysaccharidesBasement membraneBeta CellBiological PreservationCD8-Positive T-LymphocytesCell DeathCell SurvivalCell physiologyCellsComplementDendritic CellsDevelopmentDextran SulfateDextransDiabetes MellitusDiseaseEarly treatmentEffector CellEndotheliumEnvironmentExtracellular MatrixHGF geneHumanImmuneImmune ToleranceImmune systemImpairmentIn VitroInbred NOD MiceIncidenceIndividualInfiltrationInflammationInflammatoryInsulin-Dependent Diabetes MellitusKnowledgeLeadLectinLigandsLymphocyte ActivationMaintenanceMediatingMolecularMolecular WeightMusNatural regenerationPDCD1LG1 genePhenotypePolysaccharidesPrevalencePreventionPreventiveProductionPublic HealthReportingSelf ToleranceSignal TransductionSplenocyteStimulusStressStructure of beta Cell of isletT cell responseT-LymphocyteTestingTherapeuticTherapeutic EffectTissuesTreatment FactorTreatment ProtocolsUnspecified or Sulfate Ion SulfatesUp-Regulationautoreactive T cellcytokinecytotoxicdiabeticearly onsetefficacy testingimmunoregulationisletmacrophagemembermouse modelperipheral toleranceprevent
项目摘要
Type 1 diabetes (T1D), with a prevalence of ~200/100,000 and an incidence that has been increasing by 2-5%
worldwide over the past few years, poses a considerable challenge to afflicted individuals, to the development of effective prevention and treatment regimens, and to public health initiatives at large. Therapies focused on preserving functional beta cells; gaining immune tolerance; and inducing beta cell regeneration are a priority for the treatment of the disease. The sulfated polysaccharide Dextran Sulfate (DS) is a polyanionic derivative of the bacterial polysaccharide dextran. Preliminary studies from our lab suggest that low molecular weight DS (5-8kDa) is a prosurvival agent for the beta cell in vitro against cytokines and ER stress. However, the molecular mechanisms involved in these effects are unknown. In addition, whether DS protects beta cell function in a proinflammatory environment is also unknown. Upregulation of the inhibitory co-stimulatory signal PD-1/PD-L1 provides negative stimuli influencing T lymphocyte activation and promoting the maintenance of peripheral tolerance. Preliminary studies indicate that DS treatment of splenocytes in vitro leads to a significant increase in the number of DCs, B cells and macrophages expressing PD-L1. DS also increases the number of activated CD4+ and CD8+ T cells expressing PD-1. This suggests that DS could help to maintain peripheral tolerance in a setting predisposed to autoimmunity. To test the efficacy of DS for T1D treatment, we have analyzed the effect of DS in the prevention and reversal of diabetes in the NOD mouse, the spontaneous mouse model of T1D. DS treatment impairs beta cell death, preserves beta cell mass and prevents the development of T1D in pre-diabetic NOD mice. More importantly, DS treatment of early onset diabetic NOD mice reverses diabetes in ~70% of the mice. DS treatment preserves beta cell mass with intact islets surrounded by massive number of immune cells, suggesting islet infiltration impairment, decreased cytokine production and/or enhanced beta cell survival. Interestingly, treatment of NOD mice with a blocking mAb against PD-L1 completely abrogated the preventive effects of DS in diabetes development. Collectively, these studies suggest a promising therapeutic effect of DS for T1D by potentially preserving functional beta cells, gaining immune tolerance and enhancing beta cell regeneration. Our hypothesis is that DS reverses T1D by favoring the survival and maintaining the function of the beta cell in an islet inflammation environment, and by
modulating the immune system to enhance tolerance. To determine whether our hypothesis is correct, we will develop the following Specific Aims: Specific Aim 1. To determine the effect and molecular mechanisms mediated by DS on beta cell survival and function in the context of T1D. Specific Aim 2. To analyze the efficacy of dextran sulfate (DS) treatment alone or in combination with hepatocyte growth factor (HGF) for reversing diabetes in NOD mice.
Specific Aim 3. To dissect and stratify DS-induced immunomodulatory effects on human T cell responses. The proposed studies will provide significant information regarding the therapeutic potential of DS for T1D and
the cellular and molecular mechanisms involved in the beneficial effects of this sulfated polysaccharide.
1型糖尿病(T1D),患病率约为200/10万,发病率增加了2-5%
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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Adolfo Garcia-Ocana其他文献
Adolfo Garcia-Ocana的其他文献
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{{ truncateString('Adolfo Garcia-Ocana', 18)}}的其他基金
Myc Physiology in the Pancreatic Beta Cell
胰腺 Beta 细胞中的 Myc 生理学
- 批准号:
10224945 - 财政年份:2020
- 资助金额:
$ 42.38万 - 项目类别:
Myc Physiology in the Pancreatic Beta Cell
胰腺 Beta 细胞中的 Myc 生理学
- 批准号:
10399579 - 财政年份:2020
- 资助金额:
$ 42.38万 - 项目类别:
Myc Physiology in the Pancreatic Beta Cell
胰腺 Beta 细胞中的 Myc 生理学
- 批准号:
10613937 - 财政年份:2020
- 资助金额:
$ 42.38万 - 项目类别:
Protein Kinase C (PKC) Zeta and the Pancreatic Beta Cell
蛋白激酶 C (PKC) Zeta 和胰腺 Beta 细胞
- 批准号:
7992533 - 财政年份:2010
- 资助金额:
$ 42.38万 - 项目类别:
Protein Kinase C (PKC) Zeta and the Pancreatic Beta Cell
蛋白激酶 C (PKC) Zeta 和胰腺 Beta 细胞
- 批准号:
8080879 - 财政年份:2008
- 资助金额:
$ 42.38万 - 项目类别:
Protein Kinase C (PKC) Zeta and the Pancreatic Beta Cell
蛋白激酶 C (PKC) Zeta 和胰腺 Beta 细胞
- 批准号:
8577347 - 财政年份:2008
- 资助金额:
$ 42.38万 - 项目类别:
Protein Kinase C (PKC) Zeta and the Pancreatic Beta Cell
蛋白激酶 C (PKC) Zeta 和胰腺 Beta 细胞
- 批准号:
7674801 - 财政年份:2008
- 资助金额:
$ 42.38万 - 项目类别:
Hepatocyte Growth Factor and The Pancreatic Beta Cell
肝细胞生长因子和胰腺β细胞
- 批准号:
8472477 - 财政年份:2004
- 资助金额:
$ 42.38万 - 项目类别:
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