Identification and characterization of receptors targeting VGF-derived peptides.

针对 VGF 衍生肽的受体的鉴定和表征。

基本信息

项目摘要

Project summary Alzheimer's disease (AD) pathology is characterized by the accumulation of neurofibrillary tangles, dystrophic neurites, and abundant extracellular fibrils of amyloid-β peptide. However, the etiology of typical late onset AD remains elusive. Over 20 genes have been associated with late onset AD, and this heterogeneity complicates the task of discovering disease modifying treatments. The parent application proposed to: (i) identify robust molecular subtypes of AD and their characteristic molecular signatures across different layers of Omics data; (ii) characterize molecular subtypes of AD by molecular signatures, multiscale regulatory networks and key drivers; (iii) evaluate genomic and functional impact of key drivers using human iPSC derived neurons and glia; and (iv) validate key drivers of molecular networks underlying AD subtypes. Recently, efforts by the investigators in the parent grant led to the identification of the VGF gene as a key driver of the network predicted to be altered in AD. However, the molecular mechanism by which VGF modulates the network altered in AD is not well understood. It is possible that receptor systems activated by peptides derived from VGF play a crucial role in this process. Support for this comes from our previous studies of another key driver, PREPL, where we found that decreases in PREPL expression leads to decreases in levels of secreted VGF- derived peptides. Also, several VGF-derived peptides have been detected in the cerebro-spinal fluid of AD subjects and many of these peptides exhibit distinct biological activities. This suggests the existence of receptors for the VGF-derived peptides and an important role for them in AD. To date receptors for the majority of these peptides have not been definitively identified. In this supplement we propose to carry out studies to identify neuronal receptors to 18 VGF-derived peptides using the PRESTO-TANGO® assay system that contains 302 G protein-coupled receptors including 135 listed as “orphan” receptors. Identification of these receptors is a prerequisite to studies investigating the physiological significance of VGF-derived peptides to AD as well as to identifying small molecules targeting these receptors, which could become potential therapeutics for the treatment of AD.
项目总结 阿尔茨海默病(AD)的病理特征是神经原纤维缠结堆积,营养不良 神经突起和丰富的淀粉样蛋白-β多肽的胞外纤维。然而,典型晚发性AD的病因学 仍然难以捉摸。20多个基因与晚发性阿尔茨海默病相关,这种异质性使其复杂化 发现治疗疾病的方法的任务。父应用程序建议:(I)确定健壮 不同层次OMICS数据中AD的分子亚型及其特征分子特征 (2)通过分子签名、多尺度调控网络和关键字确定AD的分子亚型 (Iii)使用人类IPSC来源的神经元和胶质细胞评估关键驱动因素的基因组和功能影响; 以及(Iv)验证AD亚型下分子网络的关键驱动因素。最近,美国政府的努力 父母赠款中的调查人员确定VGF基因是网络的关键驱动因素 预计将在公元后被改变。然而,VGF调节网络的分子机制 在公元后的变化并不是很好的理解。可能的是,由来源于 VGF在这一过程中起着至关重要的作用。对这一点的支持来自我们之前对另一个关键驱动因素的研究, 在PREPL中,我们发现PREPL表达的减少会导致VGF-1分泌水平的降低。 衍生多肽。此外,在阿尔茨海默病患者的脑脊液中也检测到了几种VGF衍生肽 受试者和许多这些多肽显示出不同的生物活性。这表明了 血管生长因子衍生多肽的受体及其在AD中的重要作用。到目前为止,大多数受体 在这些多肽中,还没有得到明确的鉴定。在本补充资料中,我们建议进行以下研究: 使用Presto-Tango®检测系统鉴定18个VGF衍生多肽的神经元受体 含有302个G蛋白偶联受体,其中135个被列为“孤儿”受体。对这些的识别 受体是研究血管生长因子衍生多肽对阿尔茨海默病生理意义的前提 以及识别针对这些受体的小分子,这些小分子可能成为潜在的治疗药物 治疗阿尔茨海默病。

项目成果

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MICHELLE E EHRLICH其他文献

MICHELLE E EHRLICH的其他文献

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{{ truncateString('MICHELLE E EHRLICH', 18)}}的其他基金

Systems modeling of shared and distinct molecular mechanisms underlying comorbid Major Depressive Disorder and Alzheimer's disease
对共病重度抑郁症和阿尔茨海默病潜在的共享和不同分子机制进行系统建模
  • 批准号:
    10214197
  • 财政年份:
    2018
  • 资助金额:
    $ 16.95万
  • 项目类别:
Systems modeling of shared and distinct molecular mechanisms underlying comorbid Major Depressive Disorder and Alzheimer's disease
对共病重度抑郁症和阿尔茨海默病潜在的共享和不同分子机制进行系统建模
  • 批准号:
    10172822
  • 财政年份:
    2018
  • 资助金额:
    $ 16.95万
  • 项目类别:
Systems modeling of shared and distinct molecular mechanisms underlying comorbid Major Depressive Disorder and Alzheimer's disease
对共病重度抑郁症和阿尔茨海默病潜在的共享和不同分子机制进行系统建模
  • 批准号:
    10404989
  • 财政年份:
    2018
  • 资助金额:
    $ 16.95万
  • 项目类别:
Systems modeling of shared and distinct molecular mechanisms underlying comorbid Major Depressive Disorder and Alzheimer's disease
对共病重度抑郁症和阿尔茨海默病潜在的共享和不同分子机制进行系统建模
  • 批准号:
    9788267
  • 财政年份:
    2018
  • 资助金额:
    $ 16.95万
  • 项目类别:
Integrative Network Modeling of Cognitive Resilience to Alzheimer's Disease
阿尔茨海默病认知复原力的综合网络建模
  • 批准号:
    9439453
  • 财政年份:
    2017
  • 资助金额:
    $ 16.95万
  • 项目类别:
Integrative Network Modeling of Cognitive Resilience to Alzheimer's Disease
阿尔茨海默病认知弹性的综合网络建模
  • 批准号:
    10170187
  • 财政年份:
    2017
  • 资助金额:
    $ 16.95万
  • 项目类别:
Integrative Network Biology Approaches to Identify, Characterize and Validate Molecular Subtypes in Alzheimer's Disease
识别、表征和验证阿尔茨海默病分子亚型的综合网络生物学方法
  • 批准号:
    10251248
  • 财政年份:
    2014
  • 资助金额:
    $ 16.95万
  • 项目类别:
Integrative Network Biology Approaches to Identify, Characterize and Validate Molecular Subtypes in Alzheimer's Disease
识别、表征和验证阿尔茨海默病分子亚型的综合网络生物学方法
  • 批准号:
    10005927
  • 财政年份:
    2014
  • 资助金额:
    $ 16.95万
  • 项目类别:
Integrative Network Biology Approaches to Identify, Characterize and Validate Molecular Subtypes in Alzheimer's Disease
识别、表征和验证阿尔茨海默病分子亚型的综合网络生物学方法
  • 批准号:
    10475089
  • 财政年份:
    2014
  • 资助金额:
    $ 16.95万
  • 项目类别:
Integrative Network Biology Approaches to Identify, Characterize and Validate Molecular Subtypes in Alzheimer's Disease
识别、表征和验证阿尔茨海默病分子亚型的综合网络生物学方法
  • 批准号:
    9922436
  • 财政年份:
    2014
  • 资助金额:
    $ 16.95万
  • 项目类别:
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