Targeted Molecular Probes for Atherosclerosis Imaging and Therapy
用于动脉粥样硬化成像和治疗的靶向分子探针
基本信息
- 批准号:10554272
- 负责人:
- 金额:$ 72.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-02-15 至 2026-01-31
- 项目状态:未结题
- 来源:
- 关键词:AccountingAffinityArterial Fatty StreakAtherosclerosisBindingBiocompatible Coated MaterialsBiodistributionBiologyCCR5 geneCD44 geneCXCR3 geneCardiovascular DiseasesCellsCharacteristicsChargeChemistryClinicalComplexComplicationDetectionDevelopmentDiseaseEventEvolutionFoundationsFutureGrantHealthHumanImageImaging DeviceImmuneInflammatoryInflammatory ResponseInvestigational New Drug ApplicationLeukocyte TraffickingLipidsMissionModelingMolecular ProbesMolecular TargetMyocardial InfarctionNational Heart, Lung, and Blood InstituteOryctolagus cuniculusPathogenesisPatient-Focused OutcomesPatientsPeripheral arterial diseasePlayPolymersPositron-Emission TomographyProgressive DiseaseRadiochemistryRadiolabeledResearchRoleSpecificityStrokeSurfaceTLR2 geneTissuesTracerTranslationschemokinechemokine receptordesignhigh riskhuman diseaseimage translationimaging agentimaging approachimaging probeimprovedimproved outcomein vivomonocytemouse modelnew therapeutic targetnovelnovel diagnosticsplaque lesionprogramsreceptorscale upsuccesstargeted agenttraffickingtranslational potentialtreatment response
项目摘要
Summary
Atherosclerosis is a progressive disease characterized by the development of lipid-rich, inflammatory plaque
lesions within vessel walls. It is the underlying basis of cardiovascular diseases including myocardial infarction,
stroke, and peripheral arterial disease. However, the ability to reliably detect the vulnerable plaque and identify
high-risk patients has been a challenge. Further, there is no imaging agent to detect the eroded plaques, a less-
known subtype accounting for one third of clinical events. Chemokines and chemokine receptors play important
roles in atherosclerosis from initialization to clinical event by directing leukocyte trafficking. We have developed
chemokine receptor targeted positron emission tomography (PET) imaging agents and demonstrated the
specific detection of monocyte trafficking in vivo and track plaque progression and regression. To further
explore the potential of these imaging agents for translation, we would like to propose a research program to
develop novel PET tracers with potential to identify vulnerable plaques, detect plaque erosion, and more
importantly to track the treatment response to improve patient outcome. Specifically, we will firstly optimize the
design and synthesis of a portfolio of PET tracers targeting plaque-relevant targets including CCR2, CCR5,
CXCR3, CD44, and TLR2 to improve the radiolabeling and scale-up capability through controlled
radiochemistry and bioconjugate chemistry, and binding affinities by varying the charge, surface chemistry and
polymer coating materials. Secondly, we will perform in vivo biodistribution studies and PET imaging in
atherosclerosis progression/regression and complication mouse models, as well as rabbit atherosclerosis
models to assess the imaging specificity, sensitivity, and capability to track the immune cells in vivo and
correlation with targets expression and plaque characteristics. Thirdly, we will assess the capability of
developed imaging probes to determine treatment response for improved outcome and binding to ex vivo
human plaque tissue for future translation. We propose to submit multiple exploratory investigational new drug
application to FDA and have two PET tracers ready for human trials at the end of grant period. The
establishment of this research program will not only promote the development of targeted PET tracers for
atherosclerosis translational imaging, but also broader applications in other diseases within the NHLBI mission.
概括
动脉粥样硬化是一种进行性疾病,其特征是形成富含脂质的炎症斑块
血管壁内的病变。它是包括心肌梗塞在内的心血管疾病的根本基础
中风和外周动脉疾病。然而,能够可靠地检测易损斑块并识别
高危患者一直是一个挑战。此外,没有显像剂来检测侵蚀斑块,这是一种较少的方法。
已知亚型占临床事件的三分之一。趋化因子和趋化因子受体发挥重要作用
通过指导白细胞运输,在动脉粥样硬化从初始化到临床事件的过程中发挥作用。我们开发了
趋化因子受体靶向正电子发射断层扫描(PET)成像剂并证明了
特异性检测体内单核细胞运输并跟踪斑块进展和消退。为了进一步
探索这些显像剂的翻译潜力,我们想提出一个研究计划
开发新型 PET 示踪剂,具有识别易损斑块、检测斑块侵蚀等潜力
重要的是跟踪治疗反应以改善患者的治疗结果。具体来说,我们首先会优化
设计和合成针对斑块相关靶点的 PET 示踪剂组合,包括 CCR2、CCR5、
CXCR3、CD44 和 TLR2 通过受控提高放射性标记和放大能力
放射化学和生物共轭化学,以及通过改变电荷、表面化学和结合亲和力
高分子涂层材料。其次,我们将在体内进行生物分布研究和PET成像
动脉粥样硬化进展/消退和并发症小鼠模型,以及兔动脉粥样硬化
评估成像特异性、敏感性以及体内跟踪免疫细胞的能力的模型
与靶标表达和斑块特征的相关性。第三,我们要评估的能力
开发了成像探针来确定治疗反应以改善结果并与离体结合
用于未来翻译的人类斑块组织。我们建议提交多个探索性研究新药
向 FDA 提出申请,并在授权期结束时准备好两种 PET 示踪剂进行人体试验。这
该研究计划的建立不仅将促进靶向PET示踪剂的开发
动脉粥样硬化转化成像,而且在 NHLBI 任务内的其他疾病中也有更广泛的应用。
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)
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Yongjian Liu其他文献
Yongjian Liu的其他文献
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{{ truncateString('Yongjian Liu', 18)}}的其他基金
Targeted Molecular Probes for Atherosclerosis Imaging and Therapy
用于动脉粥样硬化成像和治疗的靶向分子探针
- 批准号:
10330956 - 财政年份:2019
- 资助金额:
$ 72.82万 - 项目类别:
Targeted Molecular Probes for Atherosclerosis Imaging and Therapy
用于动脉粥样硬化成像和治疗的靶向分子探针
- 批准号:
10088464 - 财政年份:2019
- 资助金额:
$ 72.82万 - 项目类别:
Imaging macrophage subset dynamics in inflammation
炎症中巨噬细胞亚群动态成像
- 批准号:
10715915 - 财政年份:2018
- 资助金额:
$ 72.82万 - 项目类别:
CHEMOKINE RECEPTORS BASED NANOAGENTS IMAGING ATHEROSCLEROSIS
基于趋化因子受体的动脉粥样硬化成像纳米制剂
- 批准号:
9188466 - 财政年份:2014
- 资助金额:
$ 72.82万 - 项目类别:
Regulation of GTPase activity of LRRK2 and its implication in Parkinson?s disease
LRRK2 GTPase 活性的调控及其在帕金森病中的意义
- 批准号:
7469742 - 财政年份:2008
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MEMBRANE TRAFFICKING OF A VESICULAR MONOAMINE TRANSPORTER
囊泡单胺转运蛋白的膜贩运
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7181620 - 财政年份:2004
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$ 72.82万 - 项目类别:
Membrane Trafficking of a Vesicular Monoamine Transporter
囊泡单胺转运蛋白的膜运输
- 批准号:
6980056 - 财政年份:2004
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Membrane Trafficking of Vesicular Monoamine Transporter
囊泡单胺转运蛋白的膜运输
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6723679 - 财政年份:2001
- 资助金额:
$ 72.82万 - 项目类别:
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