Model for SorCS1-mediated Diabetes with Dementia

SorCS1 介导的糖尿病伴痴呆模型

基本信息

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

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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:
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