Development of Brain MRI Contrast Agents

脑MRI造影剂的开发

基本信息

项目摘要

We have made substantial progress towards Aims 1-5, 7&8. Specifically: a) We have demonstrated that a mutant mouse transferrin receptor binding nanobody with strong pH dependent unbinding crosses the BBB in vivo approximately 500 times more effectively than a control nanobody. b) We have demonstrated that the mutant mouse transferrin receptor binding nanobody can carry other nanobodies as cargo across the mouse BBB. A tandem dimer of nanobodies that bind to the P2X7 receptor has been used as a model cargo. c) We have shown that cargo transported across the BBB can be detected in capillary depleted brain lysates and histochemically at their target sites between 1 and 16 hours after injection. d) We have demonstrated that there is a strong nonlinearity in the dose-response curve for the BBB crossing nanobodies. At doses greater than 30 nmol/kg injected intravenously, there is no greater brain accumulation of cargo. The maximum brain concentration achieved was 4.5 nM. This concentration is an order of magnitude too low for MRI detection of iron oxide nanoparticles. We therefore have decided to switch to PET imaging for further development molecular contrast imaging agents. e) We are developing methods to conjugate nanobodies to the positron emitting Copper-64 for PET scans. f) We have established a new collaboration with Dr. Dale Kiesewetter and his research group to perform PET scans in living mice at multiple time points after injection. g) We have initiated new collaborations with M Janoswki at U Maryland, D Sehlin and S. Syvanen at Uppsala U, and I Huggins at Ionis Pharmaceuticals to perform additional imaging studies using our BBB crossing nanobody constructs. h) We have established new collaborations with Dr F. Nugent at USUHS, Dr. N. Plesnila at U Munich, and Dr. F. Porreca at U Arizona to test our nanobody constructs for efficacy as BBB crossing P2X7 receptor blocking therapeutics in mouse models of TBI, stroke, and post-traumatic headache. i) Ongoing work by our collaborators at Washington University indicates that our SARS-CoV-2 nanobodies have potential for use in real time environmental surveillance of aerosols and for detection of SARS-CoV-2 in exhaled breath.
我们在目标1-5、7和8方面取得了实质性进展。具体:

项目成果

期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
High affinity nanobodies block SARS-CoV-2 spike receptor binding domain interaction with human angiotensin converting enzyme.
  • DOI:
    10.1038/s41598-020-79036-0
  • 发表时间:
    2020-12-22
  • 期刊:
  • 影响因子:
    4.6
  • 作者:
    Esparza TJ;Martin NP;Anderson GP;Goldman ER;Brody DL
  • 通讯作者:
    Brody DL
Unbiased high-content screening reveals Aβ- and tau-independent synaptotoxic activities in human brain homogenates from Alzheimer's patients and high-pathology controls.
  • DOI:
    10.1371/journal.pone.0259335
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Jiang H;Esparza TJ;Kummer TT;Brody DL
  • 通讯作者:
    Brody DL
Diffuse axonal injury has a characteristic multidimensional MRI signature in the human brain.
  • DOI:
    10.1093/brain/awaa447
  • 发表时间:
    2021-04-12
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Benjamini, Dan;Iacono, Diego;Basser, Peter J
  • 通讯作者:
    Basser, Peter J
Mapping astrogliosis in the individual human brain using multidimensional MRI.
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Alan Koretsky其他文献

Alan Koretsky的其他文献

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{{ truncateString('Alan Koretsky', 18)}}的其他基金

MRI contrast for molecular and cellular imaging of the brain
用于大脑分子和细胞成像的 MRI 对比
  • 批准号:
    8557065
  • 财政年份:
  • 资助金额:
    $ 108.06万
  • 项目类别:
Functional Imaging of The Brain
大脑功能成像
  • 批准号:
    10263021
  • 财政年份:
  • 资助金额:
    $ 108.06万
  • 项目类别:
MRI contrast for molecular and cellular imaging of the brain
用于大脑分子和细胞成像的 MRI 对比
  • 批准号:
    10263037
  • 财政年份:
  • 资助金额:
    $ 108.06万
  • 项目类别:
Development of Brain MRI Contrast Agents
脑MRI造影剂的开发
  • 批准号:
    10708637
  • 财政年份:
  • 资助金额:
    $ 108.06万
  • 项目类别:
Functional Imaging of The Brain
大脑功能成像
  • 批准号:
    10708602
  • 财政年份:
  • 资助金额:
    $ 108.06万
  • 项目类别:
MRI Engineering Core
MRI 工程核心
  • 批准号:
    10916074
  • 财政年份:
  • 资助金额:
    $ 108.06万
  • 项目类别:
Maintenance and Improvement of NINDS Infrastructure
NINDS基础设施的维护和改进
  • 批准号:
    9157600
  • 财政年份:
  • 资助金额:
    $ 108.06万
  • 项目类别:
MRI contrast for molecular and cellular imaging of the brain
用于大脑分子和细胞成像的 MRI 对比
  • 批准号:
    7735334
  • 财政年份:
  • 资助金额:
    $ 108.06万
  • 项目类别:
Maintenance and Improvement of NINDS Infrastructure
NINDS基础设施的维护和改进
  • 批准号:
    8557125
  • 财政年份:
  • 资助金额:
    $ 108.06万
  • 项目类别:
Cognitive Neuroscience Investigations Of Human Frontal Lobes
人类额叶的认知神经科学研究
  • 批准号:
    8342205
  • 财政年份:
  • 资助金额:
    $ 108.06万
  • 项目类别:

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