Schwann cell derived exosomes improve diabetic peripheral neuropathy in type II diabetic mice
雪旺细胞衍生的外泌体改善 II 型糖尿病小鼠的糖尿病周围神经病变
基本信息
- 批准号:10121320
- 负责人:
- 金额:$ 41.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-15 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AblationAffectAmericanAnimal ModelAxonBlood GlucoseCellsClinical DataCommunicationComplications of Diabetes MellitusDataDemyelinationsDevelopmentDiabetes MellitusDiabetic mouseElectronsEndosomesEngineeringFamily memberFundingGene FamilyGenesGlycosylated HemoglobinGlycosylated hemoglobin AHigh Fat DietHomeostasisHomologous GeneIntravenousInvestigationMediatingMicroRNAsMicroscopicMolecularMusNerve FibersNerve TissueNervous System PhysiologyNeurologic DysfunctionsNeurological outcomeNeuronsNeurophysiology - biologic functionNon-Insulin-Dependent Diabetes MellitusPTEN genePeripheral NervesPeripheral Nervous System DiseasesPhase I Clinical TrialsPhysiologicalPlayProteinsProteolipidsRNAResearchRoleSchwann CellsSemaphorinsSomatostatinSourceSpinal GangliaStreptozocinTestingTherapeutic EffectTranslationsTreatment EfficacyType 2 diabeticWild Type Mouseaxon injurybaseclinically relevantdb/db mousedesigndiabeticdisabilityeffective therapyexosomeimprovedintercellular communicationintravenous administrationknock-downliver functionmouse modelnanovesiclenovelnovel therapeutic interventionpre-clinicalsciatic nervetransmission process
项目摘要
Abstract:
Peripheral neuropathy is one of the major common complications of diabetes. There is a compelling need to
develop effective therapeutic approaches specifically designed to improve neurological function caused by
diabetic peripheral neuropathy (DPN). Communications between Schwann cells and sciatic nerves of dorsal root
ganglia (DRG) neurons maintain homeostasis of peripheral nerve function. Exosomes, endosome-derived nano
vesicles carry RNAs and proteins as their molecular cargo. Exosomes mediate intercellular communication by
transferring their cargo between source and recipient cells. Our preliminary data showed that treatment of type
II diabetes db/db mice with Schwann cell derived exosomes (SC-Exos) remarkably ameliorated neurological
dysfunction of DPN, which was associated with significant augmentation of intraepidermal nerve fibers and
myelinated axons of the sciatic nerve. We also found that intravenously administered SC-Exos were internalized
by Schwann cells and nerve fibers of the sciatic nerve, suggesting that SC-Exos act on Schwann cells and sciatic
nerves. Our preliminary data also showed that the SC-Exo treatment did not significantly change blood glucose
and glycosylated hemoglobin (HbA1c) levels and liver function; however, importantly, SC-Exos reversed a
network of miRNAs and proteins in the sciatic nerve tissues that mediate development of DPN. Based on these
preliminary data, using a clinically relevant mouse model of high fat diet/streptozotocin-induced Type 2 diabetes,
we propose to test the hypothesis that SC-Exos interact with Schwann cells and sciatic nerves to modulate this
network of miRNAs and proteins and thereby ameliorate DPN. We will first examine whether the miRNA cargo
of SC-Exo contribute to the therapeutic effect of SC-Exos on DPN. We will then examine whether endogenous
miRNAs in Schwann cells and in the sciatic nerve of dorsal root ganglion (DRG) enhance the therapeutic effect
of SC-Exo. Subsequently, we will examine whether engineered SC-Exos carrying elevated selected miRNAs to
suppress genes that induce axonal injury and demyelination further reduce neurological dysfunction of DPN.
Relevance Statement: Diabetic peripheral neuropathy is a major disability affecting millions of Americans. In
this proposal, employing clinically relevant animal models of diabetic peripheral neuropathy, we seek to develop
a novel therapeutic approach to treat diabetic peripheral neuropathy using exosomes derived from healthy
Schwann cells. In this proposal, we will also elucidate the molecular mechanisms by which exosomes are
therapeutically effective. This research will potentially provide the essential pre-clinical data for translation of this
novel therapeutic approach to a phase 1 clinical trial.
摘要:
周围神经病变是糖尿病的主要常见并发症之一。迫切需要
开发有效的治疗方法,专门用于改善由以下原因引起的神经功能:
糖尿病周围神经病变(DPN)。背根雪旺细胞与坐骨神经的交通联系
神经节(DRG)神经元维持外周神经功能的稳态。外泌体,内体衍生的纳米
囊泡携带RNA和蛋白质作为它们的分子货物。外泌体介导细胞间通讯,
在源细胞和受体细胞之间转移它们的货物。我们的初步数据显示,
具有雪旺细胞衍生的外泌体(SC-Exos)的II型糖尿病db/db小鼠显著改善神经功能
DPN功能障碍,这与表皮内神经纤维的显著增加有关,
坐骨神经的有髓轴突。我们还发现,静脉注射SC-外骨骼肌可以内化,
通过雪旺细胞和坐骨神经的神经纤维,表明SC-Exos作用于雪旺细胞和坐骨神经
神经我们的初步数据还显示,SC-Exo治疗没有显著改变血糖
和糖化血红蛋白(HbA 1c)水平和肝功能;然而,重要的是,SC-Exos逆转了
坐骨神经组织中介导DPN发展的miRNA和蛋白质网络。基于这些
初步数据,使用高脂饮食/链脲霉素诱导的2型糖尿病的临床相关小鼠模型,
我们建议验证SC-Exos与雪旺细胞和坐骨神经相互作用以调节这种作用的假设。
通过miRNA和蛋白质的网络,从而改善DPN。我们将首先检查miRNA货物是否
SC-Exo对糖尿病周围神经病变的治疗作用可能与SC-Exo对糖尿病周围神经病变的治疗作用有关。然后我们将研究是否内源性
雪旺细胞和坐骨神经背根节(DRG)中的miRNA增强治疗效果
关于SC-Exo随后,我们将研究是否工程化的SC-Exos携带升高的选定的miRNA,
抑制诱导轴突损伤和脱髓鞘基因进一步减少DPN的神经功能障碍。
相关性声明:糖尿病周围神经病变是影响数百万美国人的主要残疾。在
该建议采用临床相关的糖尿病周围神经病变动物模型,我们寻求开发
使用源自健康人的外泌体治疗糖尿病周围神经病变的新治疗方法
雪旺氏细胞。在这个提议中,我们还将阐明外泌体被
治疗有效。这项研究可能会提供必要的临床前数据,
一种新的治疗方法进入1期临床试验。
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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Lei Wang其他文献
Palladium-Catalyzed ortho-Acylation of Acetanilides with Aldehydes via Direct CH Bond Activation.
通过直接 C·H 键活化,钯催化乙酰苯胺与醛的邻位酰化。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
Chengliang Li;Lei Wang;Pinhua Li;Wei Zhou - 通讯作者:
Wei Zhou
KOAc-promoted alkynylation of alpha-C-H bonds of ethers with alkynyl bromides under transition-metal-free conditions
无过渡金属条件下 KOAc 促进醚的 α-C-H 键与炔基溴的炔基化
- DOI:
- 发表时间:
2014 - 期刊:
- 影响因子:3.2
- 作者:
Jiajun Zhang;Pinhua Li;Lei Wang - 通讯作者:
Lei Wang
Lei Wang的其他文献
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{{ truncateString('Lei Wang', 18)}}的其他基金
Covalent Protein Binders for Cancer Research and Therapy
用于癌症研究和治疗的共价蛋白结合剂
- 批准号:
10360531 - 财政年份:2021
- 资助金额:
$ 41.12万 - 项目类别:
Covalent Protein Binders for Cancer Research and Therapy
用于癌症研究和治疗的共价蛋白结合剂
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10179199 - 财政年份:2021
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Covalent Protein Binders for Cancer Research and Therapy
用于癌症研究和治疗的共价蛋白结合剂
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10569518 - 财政年份:2021
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$ 41.12万 - 项目类别:
TERBO BRAIN Study: Trajectories of Emotional Regulation and Behavior Outcomes and related Brain Regions And Intrinsic Networks
TERBO BRAIN 研究:情绪调节和行为结果的轨迹以及相关的大脑区域和内在网络
- 批准号:
10065446 - 财政年份:2020
- 资助金额:
$ 41.12万 - 项目类别:
TERBO BRAIN Study: Trajectories of Emotional Regulation and Behavior Outcomes and related Brain Regions And Intrinsic Networks
TERBO BRAIN 研究:情绪调节和行为结果的轨迹以及相关的大脑区域和内在网络
- 批准号:
10663934 - 财政年份:2020
- 资助金额:
$ 41.12万 - 项目类别:
TERBO BRAIN Study: Trajectories of Emotional Regulation and Behavior Outcomes and related Brain Regions And Intrinsic Networks
TERBO BRAIN 研究:情绪调节和行为结果的轨迹以及相关的大脑区域和内在网络
- 批准号:
10264955 - 财政年份:2020
- 资助金额:
$ 41.12万 - 项目类别:
Schwann cell derived exosomes improve diabetic peripheral neuropathy in type II diabetic mice
雪旺细胞衍生的外泌体改善 II 型糖尿病小鼠的糖尿病周围神经病变
- 批准号:
10413254 - 财政年份:2020
- 资助金额:
$ 41.12万 - 项目类别:
Schwann cell derived exosomes improve diabetic peripheral neuropathy in type II diabetic mice
雪旺细胞衍生的外泌体改善 II 型糖尿病小鼠的糖尿病周围神经病变
- 批准号:
10643939 - 财政年份:2020
- 资助金额:
$ 41.12万 - 项目类别:
Schwann cell derived exosomes improve diabetic peripheral neuropathy in type II diabetic mice
雪旺细胞衍生的外泌体改善 II 型糖尿病小鼠的糖尿病周围神经病变
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