Model for SorCS1-mediated Diabetes with Dementia
SorCS1 介导的糖尿病伴痴呆模型
基本信息
- 批准号:8599496
- 负责人:
- 金额:$ 36.71万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-01-15 至 2015-12-31
- 项目状态:已结题
- 来源:
- 关键词:AgingAlzheimer&aposs DiseaseAlzheimer&aposs disease riskAmyloid beta-ProteinAmyloid beta-Protein PrecursorBrainCharacteristicsComplexCultured CellsDataDementiaDiabetes MellitusDiseaseFamilyFemaleFunctional disorderGenderGene TransferGenerationsGeneticGenetic PolymorphismHumanInsulinInsulin ResistanceLinkMediatingMetabolicMetabolismModelingMolecularMusMutationNon-Insulin-Dependent Diabetes MellitusPatientsPhenotypePhosphorylationProtein PrecursorsProteinsRiskRoleSerineStructureTertiary Protein StructureTestingTransgenic MiceVacuolar Protein SortingVertebral columnViral GenesWorkamyloid peptidegenetic associationgenetic linkageglucose metabolismglucose tolerancehippocampal morphometryhypercholesterolemiainsulin tolerancelearned behavioroverexpressionprotein complexprotein metabolismprotein transportsexual dimorphismsortilintrafficking
项目摘要
SUMMARY
Type 2 diabetes mellitus (T2D or T2DM) increases the risk for Alzheimer's disease (AD), and SORCS1 is
genetically linked to both T2D and AD. We have undertaken a study of the possible role(s) for SorCS1 in
metabolism of the Alzheimer's amyloid-¿ (¿¿) precursor protein (APP), in order to define the molecular
mechanisms underlying this coordinate genetic linkage to both diseases. Overexpression of SorCS1c¿-myc
in cultured cells caused a reduction (p=0.002) in ¿¿ generation (Lane et al., 2010). Endogenous murine
A¿40 and ¿¿42 levels were increased (A¿40, p=0.044; A¿42, p=0.007) in the brains of female Sorcs1
hypomorphic mice, possibly paralleling the sexual dimorphism that is characteristic of the genetic
associations of SORCS1 with AD and DM. Since SorL1, another AD-linked Vps10-domain protein, directly
interacts with Vps35 to modulate APP metabolism, we investigated the possibility that SorCS1c¿-myc might
interact with APP, SorL1, and/or Vps35. We readily recovered SorCS1:APP, SorCS1:SorL1, and
SorCS1:Vps35 complexes from nontransgenic mouse brain. Notably, total Vps35 protein levels were
decreased by 49% (p=0.009) and total SorL1 protein levels were decreased by 29% (p=0.003) in the brains
of female Sorcs1-/- mice. We hypothesize that dysfunction of SorCS1 may contribute to both the APP/¿¿
disturbance underlying AD and the insulin/glucose metabolism disturbance underlying DM. In order to test
this hypothesis further, we propose the following specific aims: Specific Aim 1. To evaluate the importance
of SorCS1 protein interaction motifs and SorCS1/SorL1/APP complex formation on APP metabolism by: (a)
Characterizing APP metabolism in cultured cells overexpressing SorCS1; (b) Testing the effects of
mutations of protein-protein interacting motifs in the cytoplasmic and ectodomains of SorCS1 on both the
formation of tripartite SorCS1/SorL1/APP complexes and APP metabolism; (c) Testing the effect of a
putative pathogenic SorCS1 polymorphism on both the formation of tripartite SorCS1/SorL1/APP complexes
and APP metabolism; (d) Confirming the importance of functional domains identified in Aim 1aii and 1aiii by
viral gene transfer into primary cultures. Specific Aim 2. To employ Sorcs1 hypomorphic and plaque-
forming human Swedish APP/PS bigenic mice crossed with Sorcs1 hypomorphic mice for characterization
of: (i) endogenous APP metabolism; (ii) hippocampal morphometry, dendritic arborization, and spine
structure; (c) learning behavior. Aging (3 mo, 6 mo, 12 mo) effects will also be studied. Specific Aim 3. To
perform standard glucose and insulin tolerance tests and metabolic profile phenotyping of Sorcs1-/- mice
and plaque-forming" human Swedish APP/PS co-transgenic mice crossed with Sorcs1 -/- mice.
摘要
2型糖尿病(T2D或T2 DM)会增加患阿尔茨海默病(AD)的风险,而SORCS1是
基因上与T2D和AD有关。我们已经进行了一项关于SorCS1在
阿尔茨海默病淀粉样前体蛋白(APP)的代谢,以定义分子
这种机制与这两种疾病的遗传联系相协调。SorCS1c?-myc的过表达
导致世代减少(p=0.002)(Lane等人,2010年)。内源性小鼠
雌性动物大脑中A?40和A?42水平升高(A?40,p=0.044;A?42,p=0.007)。
低形态的小鼠,可能与遗传特征的性二型性平行
SORCS1与阿尔茨海默病和糖尿病的相关性自SORL1以来,另一种与AD相关的Vps10结构域蛋白直接
与VPS35相互作用调节APP代谢,我们调查了SorCS1c?-myc可能
与APP、SORL1和/或VPS35交互。我们很容易地恢复了SorCS1:App、SorCS1:SORL1和
SorCS1:来自非转基因小鼠脑的VPS35复合体。值得注意的是,总的VPS35蛋白水平是
大脑中SORL1总蛋白水平下降了29%(p=0.003),下降了49%(p=0.009)
雌性Sorcs1-/-小鼠。我们推测,SorCS1功能障碍可能与APP/?
阿尔茨海默病的潜在障碍和糖尿病的胰岛素/葡萄糖代谢障碍。为了测试
在这一假设的基础上,我们提出了以下具体目标:具体目标1.评估重要性
SorCS1蛋白相互作用基序和SorCS1/SORL1/APP复合体的形成对APP代谢的影响:(A)
鉴定APP在过表达SorCS1的培养细胞中的代谢;(B)测试
SorCS1胞质和胞外区蛋白相互作用基序的突变
三方SorCS1/SORL1/APP复合体的形成和APP代谢;(C)检测A
可能致病的SorCS1多态形成三方SorCS1/SORL1/APP复合体
和APP代谢;(D)确认目标1aii和1aiii中确定的功能结构域的重要性
病毒基因转移到原代培养物中。具体目的2.使用Sorcs1亚形和斑块-
人瑞典APP/PS双基因小鼠与Sorcs1亚型小鼠杂交的研究
研究:(I)内源性APP代谢;(Ii)海马形态计量学、树突分枝和脊椎
结构;(C)学习行为。老化(3个月、6个月、12个月)的影响也将被研究。具体目标3.至
对Sorcs1-/-小鼠进行标准的葡萄糖和胰岛素耐量试验及代谢谱表型分析
和斑块形成“人瑞典APP/PS共转基因小鼠与Sorcs1-/-小鼠杂交。
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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SAMUEL E. GANDY其他文献
SAMUEL E. GANDY的其他文献
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{{ truncateString('SAMUEL E. GANDY', 18)}}的其他基金
Proneurogenic Treatment for Amyloid or Tau-Based Neurodegeneration
针对淀粉样蛋白或 Tau 神经变性的促神经源性治疗
- 批准号:
10378457 - 财政年份:2017
- 资助金额:
$ 36.71万 - 项目类别:
Proneurogenic Treatment for Amyloid or Tau-Based Neurodegeneration
针对淀粉样蛋白或 Tau 神经变性的促神经源性治疗
- 批准号:
9911993 - 财政年份:2017
- 资助金额:
$ 36.71万 - 项目类别:
Rehab Therapy Adjunct with a Neurogenic, Mnemoactive, A-Beta-Lowering Compound
含有神经源性、记忆活性、A-β 降低化合物的康复治疗辅助剂
- 批准号:
9220567 - 财政年份:2014
- 资助金额:
$ 36.71万 - 项目类别:
Rehab Therapy Adjunct with a Neurogenic, Mnemoactive, A-Beta-Lowering Compound
含有神经源性、记忆活性、A-β 降低化合物的康复治疗辅助剂
- 批准号:
8596270 - 财政年份:2014
- 资助金额:
$ 36.71万 - 项目类别:
Rehab Therapy Adjunct with a Neurogenic, Mnemoactive, A-Beta-Lowering Compound
含有神经源性、记忆活性、A-β 降低化合物的康复治疗辅助剂
- 批准号:
9026594 - 财政年份:2014
- 资助金额:
$ 36.71万 - 项目类别:
Rehab Therapy Adjunct with a Neurogenic, Mnemoactive, A-Beta-Lowering Compound
含有神经源性、记忆活性、A-β 降低化合物的康复治疗辅助剂
- 批准号:
8825927 - 财政年份:2014
- 资助金额:
$ 36.71万 - 项目类别:
Generation and Characterization of Alzheimer Brain Cells
阿尔茨海默病脑细胞的生成和表征
- 批准号:
8370239 - 财政年份:2012
- 资助金额:
$ 36.71万 - 项目类别:
Model for SorCS1-mediated Diabetes with Dementia
SorCS1 介导的糖尿病伴痴呆模型
- 批准号:
8788636 - 财政年份:2012
- 资助金额:
$ 36.71万 - 项目类别:
Model for SorCS1-mediated Diabetes with Dementia
SorCS1 介导的糖尿病伴痴呆模型
- 批准号:
8411973 - 财政年份:2012
- 资助金额:
$ 36.71万 - 项目类别:
Model for SorCS1-mediated Diabetes with Dementia
SorCS1 介导的糖尿病伴痴呆模型
- 批准号:
8295466 - 财政年份:2012
- 资助金额:
$ 36.71万 - 项目类别: