Molecular Imaging Probes for Reporting on Vascular Oxidative Response

用于报告血管氧化反应的分子成像探针

基本信息

项目摘要

DESCRIPTION (provided by applicant): Cardiovascular disease is the major cause of mortality in developed countries claiming 870,000 deaths/year in US alone (year 2004 statistics). With cases on the rise in the developing countries as well the associated raising costs in managing the afflicted population will have global implications and urgently require paradigm-shifting approaches to diagnosis and monitoring of disease progression. In this proposal we suggest to develop and apply novel molecular imaging probes for detecting the changes in the repertoire of cell-generated mediators typical of local inflammation in the vascular wall as the early signal of cardiovascular disease progression. Myeloperoxidase (MPO, one of the components released by PMNs via triggered exocytosis) is a unique catalytically active marker of inflammation sites, implicated in progression of vascular pathologies, e.g. unstable atheroma. We previously developed and applied MR signal amplification strategy for imaging of MPO enzymatic activity using paramagnetic bisamides of GdDTPA as reducing substrates of MPO. Due to the fact that MPO binds to the cell surface and is retained at the site of inflammation, the potential applications of MPO imaging are numerous and range from stroke imaging to imaging of vascular wall pathologies. Building on our previous research applying MR and nuclear imaging to visualization of culprits of inflammation of the vascular wall we propose to perform optimization of MPO molecular imaging probe with the focus on probe stability and potential translation of our research. We also propose to design novel dual-function sensors for MPO imaging. MPO activity in vascular lesions is rate-limited by the rates of local hydrogen peroxide production. Hydrogen peroxide is a product of superoxide/hydrogen peroxide pathway activation in many cells populating blood vessel wall (PMN, monocytes and endothelial cells), which respond by activating intracellular NADPH oxidase. We propose to synthesize and test in model systems paramagnetic superoxide dismutase (SOD) mimic-MPO substrates based on chelated paramagnetic Mn(II) and Gd(III), which supply additional hydrogen peroxide, and simultaneously report on MPO activity due to the ability to bind to proteins of cell surface and extracellular matrix. We propose optimization steps, feasibility testing using radioisotope methods and toxicity testing before in vivo imaging. The proposal will pursue three major aims: 1) develop novel synthetic approaches and building blocks for optimizing myeloperoxidase reporter probes (MPO-specific paramagnetic chelates); 2) characterize the developed molecular imaging probes: enzyme reporting, dismutase mimic properties and stability in vitro; 3) perform testing of molecular probes for imaging oxidative response in vivo.
描述(由申请人提供): 心血管疾病是发达国家死亡的主要原因,仅在美国每年就有87万人死亡(2004年的统计数字)。由于发展中国家的病例也在增加,管理受影响人口的相关费用增加将产生全球影响,迫切需要改变诊断和监测疾病发展的方式。在这项建议中,我们建议开发和应用新的分子成像探针来检测作为心血管疾病进展的早期信号的血管壁局部炎症典型的细胞产生的介质的变化。髓过氧化物酶(MPO)是中性粒细胞通过胞吐作用释放的成分之一,是炎症部位独特的催化活性标记物,与血管病变的进展有关,如不稳定的动脉粥样硬化。我们以前开发并应用了MR信号放大技术,以GdDTPA的顺磁性双酰胺为MPO的还原底物,用于MPO酶活性的成像。由于MPO结合到细胞表面并被保留在炎症部位,MPO成像的潜在应用非常广泛,从中风成像到血管壁病理成像。在前人研究的基础上,我们将MR和核成像应用于血管壁炎元凶的可视化研究,我们建议对MPO分子成像探针进行优化,重点放在探针的稳定性和潜在的研究翻译上。我们还提出了设计用于MPO成像的新型双功能传感器。血管病变中MPO活性受局部过氧化氢产生速率的限制。过氧化氢是分布于血管壁的多种细胞(中性粒细胞、单核细胞和内皮细胞)通过超氧化物/过氧化氢途径激活的产物,这些细胞通过激活细胞内的NADPH氧化酶进行反应。我们建议合成并在模型体系中测试基于提供额外过氧化氢的顺磁性Mn(II)和Gd(III)的顺磁性超氧化物歧化酶(SOD)模拟MPO底物,同时报道由于能够与细胞表面和细胞外基质的蛋白质结合而产生的MPO活性。我们提出了优化步骤,使用放射性同位素方法进行可行性测试,并在活体成像之前进行毒性测试。该提案将追求三个主要目标:1)开发新的合成方法和构建块,以优化髓过氧化物酶报告探针(MPO特异性顺磁性螯合物);2)表征所开发的分子成像探针:酶报告、歧化酶模拟性质和体外稳定性;3)测试用于体内氧化反应成像的分子探针。

项目成果

期刊论文数量(1)
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 }}

Alexei A Bogdanov其他文献

Alexei A Bogdanov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('Alexei A Bogdanov', 18)}}的其他基金

Molecular fluorescence lifetime sensor of pro-inflammatory signaling in diabetes
糖尿病促炎信号传导的分子荧光寿命传感器
  • 批准号:
    8925860
  • 财政年份:
    2014
  • 资助金额:
    $ 30.63万
  • 项目类别:
Molecular fluorescence lifetime sensor of pro-inflammatory signaling in diabetes
糖尿病促炎症信号传导的分子荧光寿命传感器
  • 批准号:
    9103096
  • 财政年份:
    2014
  • 资助金额:
    $ 30.63万
  • 项目类别:
Molecular Imaging Probes for Reporting on Vascular Oxidative Response
用于报告血管氧化反应的分子成像探针
  • 批准号:
    8015205
  • 财政年份:
    2010
  • 资助金额:
    $ 30.63万
  • 项目类别:
Animal Models
动物模型
  • 批准号:
    7991940
  • 财政年份:
    2010
  • 资助金额:
    $ 30.63万
  • 项目类别:
Molecular Imaging Probes for Reporting on Vascular Oxidative Response
用于报告血管氧化反应的分子成像探针
  • 批准号:
    7761172
  • 财政年份:
    2010
  • 资助金额:
    $ 30.63万
  • 项目类别:
Molecular Imaging Probes for Reporting on Vascular Oxidative Response
用于报告血管氧化反应的分子成像探针
  • 批准号:
    8223272
  • 财政年份:
    2010
  • 资助金额:
    $ 30.63万
  • 项目类别:
Transcription Factor Reporter Technology
转录因子报告技术
  • 批准号:
    7503150
  • 财政年份:
    2008
  • 资助金额:
    $ 30.63万
  • 项目类别:
Transcription Factor Reporter Technology
转录因子报告技术
  • 批准号:
    7849683
  • 财政年份:
    2008
  • 资助金额:
    $ 30.63万
  • 项目类别:
Transcription Factor Reporter Technology
转录因子报告技术
  • 批准号:
    7649476
  • 财政年份:
    2008
  • 资助金额:
    $ 30.63万
  • 项目类别:
Molecular Imaging to Determine the Risk of Rupture of Cerebral Aneurysms
分子成像确定脑动脉瘤破裂的风险
  • 批准号:
    7532250
  • 财政年份:
    2008
  • 资助金额:
    $ 30.63万
  • 项目类别:

相似国自然基金

层出镰刀菌氮代谢调控因子AreA 介导伏马菌素 FB1 生物合成的作用机理
  • 批准号:
    2021JJ40433
  • 批准年份:
    2021
  • 资助金额:
    0.0 万元
  • 项目类别:
    省市级项目
寄主诱导梢腐病菌AreA和CYP51基因沉默增强甘蔗抗病性机制解析
  • 批准号:
    32001603
  • 批准年份:
    2020
  • 资助金额:
    24.0 万元
  • 项目类别:
    青年科学基金项目
AREA国际经济模型的移植.改进和应用
  • 批准号:
    18870435
  • 批准年份:
    1988
  • 资助金额:
    2.0 万元
  • 项目类别:
    面上项目

相似海外基金

Onboarding Rural Area Mathematics and Physical Science Scholars
农村地区数学和物理科学学者的入职
  • 批准号:
    2322614
  • 财政年份:
    2024
  • 资助金额:
    $ 30.63万
  • 项目类别:
    Standard Grant
Point-scanning confocal with area detector
点扫描共焦与区域检测器
  • 批准号:
    534092360
  • 财政年份:
    2024
  • 资助金额:
    $ 30.63万
  • 项目类别:
    Major Research Instrumentation
TRACK-UK: Synthesized Census and Small Area Statistics for Transport and Energy
TRACK-UK:交通和能源综合人口普查和小区域统计
  • 批准号:
    ES/Z50290X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 30.63万
  • 项目类别:
    Research Grant
Wide-area low-cost sustainable ocean temperature and velocity structure extraction using distributed fibre optic sensing within legacy seafloor cables
使用传统海底电缆中的分布式光纤传感进行广域低成本可持续海洋温度和速度结构提取
  • 批准号:
    NE/Y003365/1
  • 财政年份:
    2024
  • 资助金额:
    $ 30.63万
  • 项目类别:
    Research Grant
Collaborative Research: Scalable Manufacturing of Large-Area Thin Films of Metal-Organic Frameworks for Separations Applications
合作研究:用于分离应用的大面积金属有机框架薄膜的可扩展制造
  • 批准号:
    2326714
  • 财政年份:
    2024
  • 资助金额:
    $ 30.63万
  • 项目类别:
    Standard Grant
Collaborative Research: Scalable Manufacturing of Large-Area Thin Films of Metal-Organic Frameworks for Separations Applications
合作研究:用于分离应用的大面积金属有机框架薄膜的可扩展制造
  • 批准号:
    2326713
  • 财政年份:
    2024
  • 资助金额:
    $ 30.63万
  • 项目类别:
    Standard Grant
Unlicensed Low-Power Wide Area Networks for Location-based Services
用于基于位置的服务的免许可低功耗广域网
  • 批准号:
    24K20765
  • 财政年份:
    2024
  • 资助金额:
    $ 30.63万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
RAPID: Collaborative Research: Multifaceted Data Collection on the Aftermath of the March 26, 2024 Francis Scott Key Bridge Collapse in the DC-Maryland-Virginia Area
RAPID:协作研究:2024 年 3 月 26 日 DC-马里兰-弗吉尼亚地区 Francis Scott Key 大桥倒塌事故后果的多方面数据收集
  • 批准号:
    2427233
  • 财政年份:
    2024
  • 资助金额:
    $ 30.63万
  • 项目类别:
    Standard Grant
Postdoctoral Fellowship: OPP-PRF: Tracking Long-Term Changes in Lake Area across the Arctic
博士后奖学金:OPP-PRF:追踪北极地区湖泊面积的长期变化
  • 批准号:
    2317873
  • 财政年份:
    2024
  • 资助金额:
    $ 30.63万
  • 项目类别:
    Standard Grant
RAPID: Collaborative Research: Multifaceted Data Collection on the Aftermath of the March 26, 2024 Francis Scott Key Bridge Collapse in the DC-Maryland-Virginia Area
RAPID:协作研究:2024 年 3 月 26 日 DC-马里兰-弗吉尼亚地区 Francis Scott Key 大桥倒塌事故后果的多方面数据收集
  • 批准号:
    2427232
  • 财政年份:
    2024
  • 资助金额:
    $ 30.63万
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了