MR Signal Amplification for Receptor Imaging

用于受体成像的 MR 信号放大

• 批准号: 8648867
• 负责人: Alexei A Bogdanov
• 金额: $ 35.46万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8648867
• 关键词: Abnormal Cell; Adenocarcinoma; Adenocarcinoma Cell; Animals; Biochemical Reaction; Breast; Breast Adenocarcinoma; Breast Carcinoma; Cancer Model; Cancer Patient; Catheters; Cell Culture Techniques; Cell physiology; Cell surface; Cells; Clinical; Detection; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Drug Kinetics; E-Selectin; Electronics; Electrons; Endothelial Cells; Enzymes; Epidermal Growth Factor Receptor; Etiology; Funding; Generations; Goals; Gold; Heart Diseases; Human; Hydrogen Peroxide; Image; Imaging Device; Immunoglobulin Fragments; In Vitro; Injection of therapeutic agent; Investigation; Laboratory Animals; Lead; Life; Link; Magnetic Resonance Imaging; Mediating; Mediator of activation protein; Medical; Medicine; Metastatic Adenocarcinoma; Metastatic Neoplasm to the Bone; Methods; Modeling; Modification; Molecular; Molecular Target; Molecular Weight; Monitor; Neoplasm Metastasis; One-Step dentin bonding system; Osteolytic; Output; Oxidation-Reduction; Oxidoreductase; PECAM1 gene; Pathology; Patients; Peroxidases; Pharmaceutical Preparations; Phenols; Physicians; Play; Prevention; Procedures; Progress Reports; Proteins; Protocols documentation; Publications; Reaction; Receptor Signaling; Research; Resolution; Role; Safety; Schedule; Scientist; Seminal; Signal Transduction; Site; Specificity; Surface; TACSTD2 gene; Techniques; Testing; Time; Tissues; Translating; Work; base; bone; cofactor; density; design; enzyme activity; enzyme substrate; epidermal growth factor receptor VIII; glucose oxidase; imaging probe; improved; in vivo; interstitial; malignant breast neoplasm; meetings; mimetics; molecular imaging; nanoparticle; neoplastic cell; novel; novel diagnostics; overexpression; pre-clinical; public health relevance; receptor; receptor binding; receptor expression; response; theranostics; tool; tumor

The MRamp strategy was designed with the goal of improving the molecular sensitivity of MR imaging by modulating the MR signal output on two levels simultaneously: 1) specificity: the use of a pair of the receptor- targeted enzymes that co-localize in the specific tissue compartment and enable rapid modification of low molecular weight paramagnetic substrates resulting in their local retention at the reaction site; and 2) sensitivity: this local retention results in rapid accumulation of paramagnetic substrates that gives rise to an amplified MR signal generated by both the high density and increased relaxivity of the paramagnetic products of the enzymatic reaction. Our seminal work eventually culminated in: 1) imaging of endogenous peroxidases (e.g. myeloperoxidase) in many disease states by several research groups, and; 2) imaging of receptor expression in cancer models. In this renewal we propose to harness the MRamp technique to meet the challenges of MR molecular imaging of epidermal growth factor (EGF) receptor and EpCAM cell-surface molecule as potential markers for targeted imaging of metastasis. Human epidermal growth factor receptor (EGFR) is overexpressed in 15-20% of all breast carcinomas and its expression level correlates with the ability of breast cancer to metastasize. EGFR signaling is linked to bone degradation, which often occurs in patients with breast cancer. The goal of this proposal is to continue our research aimed at developing and validating novel imaging probes which can be applied to detection of in vivo changes in EGFR expression in bone metastases of mammary adenocarcinoma (MAC) using MRI (high resolution) and ¿PET (high sensitivity) techniques. This work is expected to be readily translatable to the design of a new diagnostic capability (monitoring levels of EGFR/EpCAM expression). MAC frequently overexpresses EpCAM while EGFR expression in metastasis is a viable marker for the development of osteolytic tumors. MRamp is one of the few available techniques that would make the detection of the coexpression of two protein markers (receptors) feasible. This work will also provide a new experimental tool for clinical and preclinical investigations regarding the etiology and pathology of metastatic adenocarcinoma.

设计MRamp策略的目的是通过以下方式提高MR成像的分子灵敏度： 同时在两个水平上调制MR信号输出：1）特异性：使用一对受体- 靶向的酶，共定位在特定的组织区室，并能够快速修改低 分子量顺磁性底物，导致它们在反应位点的局部保留;和2） 灵敏度：这种局部保留导致顺磁性底物的快速积累， 由顺磁产物的高密度和增加的弛豫性产生的放大的MR信号 酶促反应。我们的开创性工作最终达到高潮：1）内源性过氧化物酶的成像 (e.g.髓过氧化物酶）在许多疾病状态中的作用，以及; 2）受体成像 在癌症模型中的表达。在这次更新中，我们建议利用MRamp技术来满足 表皮生长因子（EGF）受体和EpCAM细胞表面MR分子成像的挑战 分子作为转移的靶向成像的潜在标志物。人表皮生长因子受体 EGFR在15-20%的乳腺癌中过表达，其表达水平与乳腺癌的细胞增殖能力相关。 乳腺癌转移的几率EGFR信号传导与患者经常发生的骨降解有关 患有乳腺癌这项提案的目标是继续我们的研究，旨在开发和验证 可用于检测骨中EGFR表达的体内变化的新型成像探针 使用MRI（高分辨率）和º PET（高灵敏度）检测乳腺癌（MAC）转移 技术.这项工作预计将很容易转化为一个新的诊断能力的设计 （监测EGFR/EpCAM表达水平）。MAC经常过表达EpCAM，而EGFR 在转移中的表达是溶骨性肿瘤发展的可行标志物。Mramp是为数不多的 现有的技术可以检测两种蛋白质标记物（受体）的共表达， 可行这项工作也将为临床和临床前研究提供一个新的实验工具， 转移性腺癌的病因和病理学。