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.
总结
2型糖尿病(T2 D或T2 DM)增加阿尔茨海默病(AD)的风险,SORCS 1是
与T2 D和AD都有遗传联系。我们已经对SorCS 1在以下方面可能发挥的作用进行了研究:
阿尔茨海默氏症淀粉样蛋白前体蛋白(APP)的代谢,以确定分子
这两种疾病的协调遗传联系的潜在机制。SorCS 1c-myc的过表达
在培养的细胞中,引起第二代的减少(p=0.002)(Lane等人,2010年)。内源鼠
在雌性Sorcs的大脑中,A <$40和A <$42水平增加(A <$40,p=0.044; A <$42,p=0.007)1
亚型小鼠,可能与遗传特征的性二型性平行。
SORCS 1与AD和DM的相关性。由于SorL 1,另一个AD连接的Vps 10结构域蛋白,直接
与Vps 35相互作用以调节APP代谢,我们研究了SorCS 1c <$-myc可能
与APP、SorL 1和/或Vps 35交互。我们很容易地回收了SorCS 1:APP,SorCS 1:SorL 1,
来自非转基因小鼠脑的SorCS 1:Vps 35复合物。值得注意的是,总Vps 35蛋白水平为
降低49%(p=0.009),大脑中总SorL 1蛋白水平降低29%(p=0.003
雌性Sorcs 1-/-小鼠的死亡率。我们假设SorCS 1的功能障碍可能导致APP/APP 1/APP 2的表达。
AD基础的胰岛素/葡萄糖代谢紊乱和DM基础的胰岛素/葡萄糖代谢紊乱。为了测试
根据这一假设,我们提出了以下具体目标:具体目标1。为了评估
SorCS 1蛋白相互作用基序和SorCS 1/SorL 1/APP复合物形成对APP代谢的影响:
表征过表达SorCS 1的培养细胞中的APP代谢;(B)测试
SorCS 1的胞质和胞外域中蛋白质-蛋白质相互作用基序的突变,
三重SorCS 1/SorL 1/APP复合物的形成和APP代谢;(c)测试
推定的致病性SorCS 1多态性对SorCS 1/SorL 1/APP三元复合物的形成均具有影响
和APP代谢;(d)通过以下方式重申目标1aii和1aiii中鉴定的功能结构域的重要性:
将病毒基因转移到原代培养物中。具体目标2。使用半变形巫师和噬斑巫师-
形成人瑞典APP/PS双基因小鼠与Sorcs 1亚型小鼠杂交用于表征
(i)内源性APP代谢;(ii)海马形态学,树突状分支和棘
(3)学习行为。还将研究老化(3个月、6个月、12个月)的影响。具体目标3。到
对Sorcs 1-/-小鼠进行标准葡萄糖和胰岛素耐量试验和代谢谱表型分析
以及与Sorcs 1-/-小鼠杂交的“噬斑形成”人瑞典APP/PS共转基因小鼠。
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: