Molecular Imaging of Protein Glycosylation in Living Subjects

活体蛋白质糖基化的分子成像

• 批准号: 8416133
• 负责人: Adam de la Zerda
• 金额: $ 39.26万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-25 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416133
• 关键词: Algorithms; Animals; Behavior; Biochemistry; Biological; Biological Markers; Cancer Biology; Cancer Model; Cancer Patient; Carbon Nanotubes; Chemicals; Chemistry; Clinical; Complex; Contrast Media; Development; Disease; Disease model; Early Diagnosis; Environment; Epitopes; Glycobiology; Glycoproteins; Gold; Health; Image; Imaging Device; Imaging technology; Integrins; Label; Life; Light; Malignant Neoplasms; Malignant neoplasm of prostate; Medical; Medical Imaging; Modification; Monitor; Mus; Neoplasm Metastasis; Neurologic; Optical Coherence Tomography; Optics; Organ; Patients; Pattern; Play; Polysaccharides; Post-Translational Protein Processing; Postdoctoral Fellow; Prostatectomy; Protein Glycosylation; Proteins; Resolution; Role; Sialic Acids; Signal Transduction; System; Techniques; Three-Dimensional Imaging; Time; Tissues; Translating; Validation; angiogenesis; base; cancer type; computerized data processing; imaging modality; in vivo; information gathering; insight; instrument; instrumentation; interest; molecular imaging; mouse model; nanoparticle; nanorod; nervous system disorder; next generation; novel; novel therapeutics; particle; reconstruction; sialylation; spatiotemporal; sugar; tissue phantom; tool; tumor; tumor progression

DESCRIPTION (provided by applicant): The broad objective of this project is to develop instrumentation and chemistry imaging technologies to advance the study of protein glycosylation in living subjects. Protein glycosylation is the most abundant and complex posttranslational modification (PTM). Changes in protein glycosylation have been correlated with cancer progression, neurological disorders and many other diseases. Moreover, glycans are dynamic in time, space and environment. Hence, in order to truly study the function of glycans in health and disease, their dynamic spatiotemporal behavior should be imaged in living subjects, and where relevant, in the context of the proteins they modify. However, current in vivo imaging tools have limited spatial and temporal resolutions and are not capable of visualizing protein glycosylations. We propose a novel molecular imaging modality that would allow imaging the spatiotemporal behavior of glycans in living murine cancer models. Such tools would advance the field of glycobiology, accelerate the discovery and validation of new disease biomarkers, and bridge traditional biochemistry with high-level biological disease models. Beyond the basic cancer biology prospects, imaging the tumor glycome may provide an indication on the tumor aggressiveness. Such information will guide treatment decisions of diseases such as prostate cancer (advise patients on prostatectomy versus "active surveillance") as well as other cancer types. We will optimize a new imaging instrument we developed based on optical coherence tomography, to allow visualizing nanoparticle-based contrast agents in living tissues with ultrahigh sensitivities (Aim 1). Second, we will synthesize two new classes of nanoparticle imaging agents: the first for targeting and visualizing a specific glycan epitope (Aim 2a) and the second for targeting and visualizing a specific glycan epitope on a specific protein of interest (Aim 2b). The first class of imaging agents will be used to visualize levels of sialic acid, an important glycan associated with cancer progression and metastasis. The second class will be used to monitor sialic acid levels on ¿v¿3 integrin. The sialylation of ¿v¿3 integrin may play a vital role in promoting angiogenesis and metastasis, but is currently poorly understood. We will validate the new imaging instrumentation and imaging agents in orthotopic prostate cancer mouse models and study the spatiotemporal patterns of sialic acid and sialylated ¿v¿3 integrin during prostate cancer progression and metastasis (Aim 3). PUBLIC HEALTH RELEVANCE: We aim to develop next-generation medical imaging technologies that would allow looking inside organs and gathering information on which molecules are activated during prostate cancer progression. This imaging technology may provide both new basic understanding on cancer development, and clinical tools to aid in early detection and better treatment management of cancer patients. By imaging certain sugar molecules in prostate cancer, we aim to determine the tumor aggressiveness and provide clinical insights for deciding between performing prostatectomy versus "active surveillance".

描述（由申请人提供）：该项目的总体目标是开发仪器和化学成像技术，以推进活体蛋白质糖基化的研究。蛋白质糖基化是蛋白质糖基化中最丰富和最复杂的翻译后修饰（PTM）。此外，聚糖在时间、空间和环境中都是动态的，因此，为了真正研究聚糖在健康和疾病中的功能，它们的动态。时空行为应该在活体受试者中进行成像，并且在相关的情况下，在它们修饰的蛋白质的背景下进行成像。然而，当前的体内成像工具的空间和时间分辨率有限，并且无法可视化蛋白质糖基化。允许在活体小鼠癌症模型中对聚糖的时空行为进行成像的模式将推动糖生物学领域的发展，加速新疾病生物标志物的发现和验证，并将传统生物化学与高水平的生物化学联系起来。除了基本的癌症生物学前景之外，肿瘤糖组成像还可以提供肿瘤侵袭性的指示，这些信息将指导前列腺癌等疾病的治疗决策（建议患者进行前列腺切除术还是“主动监测”）。我们将优化我们开发的基于光学相干断层扫描的新型成像仪器，以实现超高灵敏度的活体组织中基于纳米颗粒的造影剂的可视化（目标 1）。纳米颗粒成像剂：第一个用于靶向和可视化特定聚糖表位（Aim 2a），第二个用于靶向和可视化特定目标蛋白质上的特定聚糖表位（Aim 2b）。可视化唾液酸水平，这是一种与癌症进展和转移相关的重要聚糖，第二类将用于监测 ¿ v¿ 3 整合素的唾液酸化。 v¿ 3 整合素可能在促进血管生成和转移中发挥重要作用，但目前人们对此知之甚少。我们将在原位前列腺癌小鼠模型中验证新的成像仪器和成像剂，并研究唾液酸和唾液酸化的时空模式。 v¿前列腺癌进展和转移期间的 3 整合素（目标 3）。 公共健康相关性：我们的目标是开发下一代医学成像技术，能够观察器官内部并收集有关前列腺癌进展过程中哪些分子被激活的信息。这种成像技术可以提供对癌症发展的新的基本了解，并提供临床工具。通过对前列腺癌中的某些糖分子进行成像，帮助癌症患者进行早期检测和更好的治疗管理，我们的目标是确定肿瘤的侵袭性，并为决定进行前列腺切除术还是“主动监测”提供临床见解。