Amyloid beta peptides and type-2 diabetes sequelae synergistically inhibit insulin signaling and trafficking at the blood brain barrier
淀粉样β肽和2型糖尿病后遗症协同抑制血脑屏障的胰岛素信号传导和运输
基本信息
- 批准号:10346468
- 负责人:
- 金额:$ 54.97万
- 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:2022-03-01 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:APP-PS1AddressAlzheimer&aposs DiseaseAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer&aposs disease riskAmyloid beta-ProteinAutomobile DrivingAutophagocytosisBlood - brain barrier anatomyBrainCerebrovascular CirculationClinicalComplexCoupledDataDefectDevelopmentDiabetes MellitusDiseaseDown-RegulationEarly Onset Alzheimer DiseaseEndocytosisEndotheliumEpidemiologyEtiologyExhibitsExocytosisFlow CytometryFunctional disorderGoalsHealthHemorrhageHigh Fat DietImageImpairmentInsulinInsulin ReceptorInsulin ResistanceKineticsKnowledgeLabelMetabolicMethodsMissionModelingMolecularMonitorMusNon-Insulin-Dependent Diabetes MellitusObesityPathologicPathway interactionsPeptidesPharmaceutical PreparationsPhasePhysiologicalPlasmaProtein ArrayPublic HealthResearchSNAP receptorSignal TransductionStrokeTechniquesTestingTotal Internal Reflection FluorescentUnited States National Institutes of HealthWestern BlottingWild Type MouseWorkX-Ray Computed Tomographyaging populationbaseblood-brain barrier functionbrain parenchymacerebral microvasculaturecerebrovascularcognitive changecombatdb/db mouseimaging modalityinhibitorinnovationinsulin signalingmonolayermouse modelnovel therapeutic interventionnovel therapeuticsoverexpressionreceptor expressionsingle photon emission computed tomographysynergismtargeted treatmenttraffickingtranscytosisuptake
项目摘要
PROJECT SUMMARY
Type-2 diabetes mellitus (T2DM) sequelae damage the cerebral microvasculature and augment Alzheimer's
pathology by inducing brain insulin resistance characterized by sub-physiological insulin levels and impaired
insulin-signaling in the brain. Conversely, soluble amyloid beta (sAβ) peptides that accumulate in the plasma
and brain during Alzheimer's progression exacerbate the impact of T2DM and aggravate brain insulin
resistance. A critical need exists to identify how T2DM sequelae and sAβ exposure inhibit insulin delivery to
the brain and intensify brain insulin resistance. The long-term goal is to elucidate cerebrovascular and
metabolic contributions to Alzheimer's disease and facilitate the development of novel therapeutic
interventions. The overall objective in this application is to determine the combined effects of T2DM sequelae
and sAβ on insulin delivery to the brain and to identify the underlying cellular and molecular mechanisms. The
central hypothesis is that T2DM sequelae and sAβ peptides perturb insulin signaling/trafficking at the
cerebrovascular endothelium [referred to as the blood brain barrier (BBB)] and reduce insulin delivery to the
brain. It is also hypothesized that these effects are further aggravated by the pathological synergism between
T2DM sequelae and sAβ. The rationale for the proposed research is that a mechanistic understanding of how
sAβ exposure and T2DM sequelae disrupt brain insulin delivery will allow us to develop novel therapeutic
strategies to address brain insulin resistance in Alzheimer's disease and T2DM. Guided by preliminary data,
the following three specific aims are proposed: 1) Determine the effect of T2DM sequelae on insulin
trafficking/signaling at the BBB; 2) Determine the effects of sAβ alone and in conjunction with T2DM sequelae
on insulin trafficking/signaling at the BBB; and 3) Identify insulin trafficking pathways at the BBB, vulnerable
to sAβ exposure and impaired insulin signaling. Under the first and second aims, dynamic SPECT/CT imaging
will be used to characterize insulin uptake kinetics at the BBB in mouse models that exhibit T2DM and
Alzheimer's sequelae. Moreover, the dysregulation in insulin signaling at the BBB will be captured by reverse
phase protein arrays. For the third aim, flow cytometry and TIRF microscopy will be used to determine the
effects of sAβ ± insulin signaling inhibitors on insulin transcytosis in BBB monolayers. The proposed research
is potentially innovative because it employs dynamic imaging methods coupled with quantitative modeling
techniques to capture changes in insulin trafficking kinetics at the BBB in T2DM and Alzheimer's mouse
models. The proposed research is significant because the contribution it is expected to have broad translational
importance in repurposing existing drugs to treat brain insulin resistance and in identifying candidate targets
to discover novel drugs. Upon completion of the work, the new knowledge generated is expected to have an
important positive impact by facilitating the identification of novel therapeutic strategies to combat brain
insulin resistance in Alzheimer's patients with T2DM.
项目概要
2 型糖尿病 (T2DM) 后遗症会损害脑微血管并加重阿尔茨海默病
通过诱导大脑胰岛素抵抗来病理学,其特征是胰岛素水平亚生理水平和受损
大脑中的胰岛素信号传导,可溶性β淀粉样蛋白(sAβ)肽在血浆中积累。
阿尔茨海默氏症进展期间的大脑和大脑会加剧 T2DM 的影响并加剧脑胰岛素水平
迫切需要确定 T2DM 后遗症和 sAβ 暴露如何抑制胰岛素输送。
长期目标是阐明脑血管和胰岛素抵抗。
代谢对阿尔茨海默病的贡献并促进新疗法的开发
本申请的总体目标是确定 T2DM 后遗症的综合影响。
和 sAβ 对胰岛素输送到大脑的影响,并确定潜在的细胞和分子机制。
中心假设是 T2DM 后遗症和 sAβ 肽会扰乱胰岛素信号传导/运输
脑血管内皮[称为血脑屏障(BBB)]并减少胰岛素输送
也有人指出,这些影响因两者之间的病理协同作用而进一步加剧。
T2DM 后遗症和 sAβ 所提出的研究的基本原理是对如何发生的机制的理解。
sAβ 暴露和 T2DM 后遗症会扰乱大脑胰岛素输送,这将使我们能够开发新的治疗方法
以初步数据为指导,解决阿尔茨海默病和 T2DM 中的大脑胰岛素抵抗问题。
提出以下三个具体目标: 1) 确定 T2DM 后遗症对胰岛素的影响
BBB 的转运/信号传导;2) 确定 sAβ 单独的作用以及与 T2DM 后遗症联合作用的作用
BBB 的胰岛素贩运/信号传导;以及 3) 确定 BBB 的胰岛素贩运途径,易受攻击
第一个和第二个目标是动态 SPECT/CT 成像。
将用于表征表现出 T2DM 和
此外,阿尔茨海默病的后遗症将被反向捕捉到 BBB 的胰岛素信号失调。
对于第三个目标,将使用流式细胞术和 TIRF 显微镜来确定
sAβ ± 胰岛素信号抑制剂对 BBB 单层胰岛素转胞吞作用的影响。
具有潜在的创新性,因为它采用动态成像方法与定量建模相结合
捕获 T2DM 和阿尔茨海默病小鼠 BBB 胰岛素运输动力学变化的技术
拟议的研究意义重大,因为它的贡献预计将具有广泛的转化作用。
重新利用现有药物治疗脑胰岛素抵抗和确定候选靶点的重要性
发现新药物。工作完成后,所产生的新知识预计将具有一定的应用价值。
通过促进识别新的治疗策略来对抗大脑产生重要的积极影响
患有 T2DM 的阿尔茨海默病患者的胰岛素抵抗。
项目成果
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KARUNYA KUMAR KANDIMALLA其他文献
KARUNYA KUMAR KANDIMALLA的其他文献
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{{ truncateString('KARUNYA KUMAR KANDIMALLA', 18)}}的其他基金
Amyloid beta peptides and type-2 diabetes sequelae synergistically inhibit insulin signaling and trafficking at the blood brain barrier
淀粉样β肽和2型糖尿病后遗症协同抑制血脑屏障的胰岛素信号传导和运输
- 批准号:
10573248 - 财政年份:2022
- 资助金额:
$ 54.97万 - 项目类别:
Uptake Mechanisms and Degradation of Amyloid Beta Protein in Neurons (pilot)
神经元中β淀粉样蛋白的摄取机制和降解(试点)
- 批准号:
7283488 - 财政年份:2007
- 资助金额:
$ 54.97万 - 项目类别:
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