High Throughput Screening for compounds reducing cell surface prion protein

高通量筛选减少细胞表面朊病毒蛋白的化合物

基本信息

  • 批准号:
    8404112
  • 负责人:
  • 金额:
    $ 4.95万
  • 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:
    2012-07-15 至 2014-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The project aims at identifying small-molecule compounds reducing or abolishing expression of prion protein (PrP) at the cell surface through a high-throughput screening (HTS) program. Prion diseases are transmisible neurodegenerative diseases caused by misfolding of PrP. There is no cure for these rare, fatal and, from a therapeutic standpoint, neglected diseases. PrP is essential for prion replication but dispensable for the host, thus constituting an ideal target for therapeutic intervention. Depleting PrP from th cell surface is sufficient to abrogate prion replication. Therefore, in collaboration with Dr. Weissmann, we developed an assay to screen for compounds able to reduce or abolish PrP expression at the cell surface. The primary assay is currently in a 384-well format and fulfills HTS readiness criteria as assessed by statistical parameters and successful preliminary screening of the US Drug Collection. We now propose to transfer the assay to the Molecular Libraries Production Centers Network (MLPCN), miniaturize and optimize the assay for the 1536- well format and screen the Molecular Libraries Small Molecule Repository (MLSMR). We will then implement secondary assays to remove false positive hits (toxicity assay), confirm suppression of cell surface PrP on different neuronal cells (orthogonal assays) and prioritize hits according to their capacity to prevent and cure prion infection in cell culture. Tertiary assays wil consist in determining the specificity of the compound for PrP versus other cell surface proteins and determining its mode of action (PrP synthesis, degradation or trafficking to the plasma membrane). Medicinal chemistry will be conducted by Dr. William Roush to enhance potency and specificity of selected compounds. These studies are directly relevant to the NIH program announcement PAR-09-129 ("Solicitation of Assays for High Throughput Screening (HTS) in the Molecular Libraries Probe Production Centers Network (MLPCN). Assay miniaturization and screening will be performed at the MLPCN laboratory of Scripps Florida led by Peter Hodder. The outcome of the project will be not only compounds for therapeutical development but also a collection of molecular probes to study PrP biosynthetic and cellular trafficking pathways. Follow-up studies, which are outside the scope of the proposal, will determine primary molecular targets of selected compounds, study the role of these targets in PrP metabolism, continue SAR and test the best compound(s) in mouse prion infection models in order to generate a candidate for pre-clinical development. Given that PrP mediates, at least in part, A¿ oligomer-induced neurotoxicity, our approach may impact not only prion diseases, but also Alzheimer's disease.
项目描述(由申请人提供):该项目旨在通过高通量筛选(HTS)程序鉴定细胞表面减少或消除朊病毒蛋白(PrP)表达的小分子化合物。朊病毒疾病是由PrP错误折叠引起的传染性神经退行性疾病。从治疗的角度来看,这些罕见的、致命的、被忽视的疾病是无法治愈的。PrP对朊病毒复制至关重要,但对宿主来说是必不可少的,因此是治疗干预的理想靶点。从细胞表面消耗PrP足以消除朊病毒复制。因此,与Weissmann博士合作,我们开发了一种检测方法来筛选能够减少或消除细胞表面PrP表达的化合物。初步分析目前采用384孔格式,通过统计参数和成功的美国药物收集初步筛选评估,符合HTS准备标准。我们现在建议将该分析转移到分子文库生产中心网络(MLPCN),小型化和优化1536孔格式的分析,并筛选分子文库小分子库(MLSMR)。然后,我们将实施二次分析,以消除假阳性命中(毒性试验),确认不同神经元细胞表面PrP的抑制(正交试验),并确定命中的优先级

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Corinne Ida Lasmezas其他文献

Corinne Ida Lasmezas的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Corinne Ida Lasmezas', 18)}}的其他基金

Development of a lead candidate for the treatment of Alzheimer's disease
开发治疗阿尔茨海默病的主要候选药物
  • 批准号:
    10553082
  • 财政年份:
    2022
  • 资助金额:
    $ 4.95万
  • 项目类别:
Development of a lead candidate for the treatment of Alzheimer's disease
开发治疗阿尔茨海默病的主要候选药物
  • 批准号:
    10706549
  • 财政年份:
    2022
  • 资助金额:
    $ 4.95万
  • 项目类别:
Mode of action of a neuroprotective compound
神经保护化合物的作用方式
  • 批准号:
    9234602
  • 财政年份:
    2016
  • 资助金额:
    $ 4.95万
  • 项目类别:
High-throughput screening for NAD+-replenishing neuroprotective compounds
高通量筛选 NAD 补充神经保护化合物
  • 批准号:
    9096250
  • 财政年份:
    2014
  • 资助金额:
    $ 4.95万
  • 项目类别:
High-throughput screening for NAD+-replenishing neuroprotective compounds
高通量筛选 NAD 补充神经保护化合物
  • 批准号:
    8760591
  • 财政年份:
    2014
  • 资助金额:
    $ 4.95万
  • 项目类别:
High-throughput screening for NAD+-replenishing neuroprotective compounds
高通量筛选 NAD 补充神经保护化合物
  • 批准号:
    8860257
  • 财政年份:
    2014
  • 资助金额:
    $ 4.95万
  • 项目类别:
Genome-wide screening for effectors of toxic prion protein-induced neuronal death
全基因组筛选有毒朊病毒蛋白诱导神经元死亡的效应子
  • 批准号:
    8428325
  • 财政年份:
    2012
  • 资助金额:
    $ 4.95万
  • 项目类别:
Genome-wide screening for effectors of toxic prion protein-induced neuronal death
全基因组筛选有毒朊病毒蛋白诱导神经元死亡的效应子
  • 批准号:
    8531365
  • 财政年份:
    2012
  • 资助金额:
    $ 4.95万
  • 项目类别:
High Throughput Screening for compounds reducing cell surface prion protein
高通量筛选减少细胞表面朊病毒蛋白的化合物
  • 批准号:
    8507710
  • 财政年份:
    2012
  • 资助金额:
    $ 4.95万
  • 项目类别:

相似国自然基金

新型F-18标记香豆素衍生物PET探针的研制及靶向Alzheimer's Disease 斑块显像研究
  • 批准号:
    81000622
  • 批准年份:
    2010
  • 资助金额:
    20.0 万元
  • 项目类别:
    青年科学基金项目
阿尔茨海默病(Alzheimer's disease,AD)动物模型构建的分子机理研究
  • 批准号:
    31060293
  • 批准年份:
    2010
  • 资助金额:
    26.0 万元
  • 项目类别:
    地区科学基金项目
跨膜转运蛋白21(TMP21)对引起阿尔茨海默病(Alzheimer'S Disease)的γ分泌酶的作用研究
  • 批准号:
    30960334
  • 批准年份:
    2009
  • 资助金额:
    22.0 万元
  • 项目类别:
    地区科学基金项目

相似海外基金

A Possible Association Between Insulin and Alzheimer?s Disease: Examining the Consequences of Altered Insulin Signalling on the Expression of Human Amyloid-Beta in Caenorhabditis elegans
胰岛素与阿尔茨海默氏病之间的可能关联:检查胰岛素信号改变对秀丽隐杆线虫中人类β淀粉样蛋白表达的影响
  • 批准号:
    428670
  • 财政年份:
    2019
  • 资助金额:
    $ 4.95万
  • 项目类别:
    Studentship Programs
Nitration of Amyloid beta Alzheimer 's disease
β 淀粉样蛋白的硝化 阿尔茨海默病
  • 批准号:
    316914751
  • 财政年份:
    2016
  • 资助金额:
    $ 4.95万
  • 项目类别:
    Research Grants
Effects of Latrepirdine on beta amyloid clearance, aggregation and neurodegeneration in Alzheimer�s disease
拉曲吡啶对阿尔茨海默病β淀粉样蛋白清除、聚集和神经变性的影响
  • 批准号:
    nhmrc : 1009295
  • 财政年份:
    2011
  • 资助金额:
    $ 4.95万
  • 项目类别:
    NHMRC Project Grants
An investigation of the role of brain amyloid in cognition, brain atrophy and Alzheimer s disease in Down s syndrome
脑淀粉样蛋白在唐氏综合症认知、脑萎缩和阿尔茨海默病中作用的研究
  • 批准号:
    G1002252/1
  • 财政年份:
    2011
  • 资助金额:
    $ 4.95万
  • 项目类别:
    Research Grant
DECREASED CLEARANCE OF CNS AMYLOID-? IN ALZHEIMER?S DISEASE
中枢神经系统淀粉样蛋白清除率降低?
  • 批准号:
    8361468
  • 财政年份:
    2011
  • 资助金额:
    $ 4.95万
  • 项目类别:
Studies of an early stage amyloid formation for Parkinson`s Disease casual protein.
帕金森病休闲蛋白的早期淀粉样蛋白形成的研究。
  • 批准号:
    20550083
  • 财政年份:
    2008
  • 资助金额:
    $ 4.95万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Chemical crosslinking of helical form of amyloid-beta for the study of Alzheimer`s disease
β-淀粉样蛋白螺旋形式的化学交联用于阿尔茨海默氏病的研究
  • 批准号:
    318045-2005
  • 财政年份:
    2005
  • 资助金额:
    $ 4.95万
  • 项目类别:
    Postgraduate Scholarships - Master's
In vivo imaging of beta-amyloid plaques in Alzheimer´s disease via positron emission tomography (PET)
通过正电子发射断层扫描 (PET) 对阿尔茨海默病中的 β-淀粉样斑块进行体内成像
  • 批准号:
    5405697
  • 财政年份:
    2003
  • 资助金额:
    $ 4.95万
  • 项目类别:
    Research Grants
Functional studies on a neuroprotective activity of the amyloid precursor protein of Alzheimer s disease.
阿尔茨海默病淀粉样前体蛋白的神经保护活性的功能研究。
  • 批准号:
    nhmrc : 145761
  • 财政年份:
    2001
  • 资助金额:
    $ 4.95万
  • 项目类别:
    NHMRC Project Grants
The neuroanatomy of Amyloid ß-Protein desposition in Alzheimer´s disease
阿尔茨海默病中淀粉样蛋白沉积的神经解剖学
  • 批准号:
    5326596
  • 财政年份:
    2001
  • 资助金额:
    $ 4.95万
  • 项目类别:
    Research Grants
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了