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（由应用提供）：该项目的广泛目的是开发仪器和化学成像技术，以推动生命受试者中蛋白质糖基化的研究。蛋白质糖基化是最丰富，最复杂的翻译后修饰（PTM）。蛋白质糖基化的变化与癌症进展，神经系统疾病和许多其他疾病有关。此外，聚糖在时间，空间和环境上是动态的。因此，为了真正研究聚糖在健康和疾病中的功能，应在其修饰的蛋白质的背景下对生物中的动态空间行为进行成像。但是，当前的体内成像工具具有有限的空间和临时分辨率，并且无法可视化蛋白质糖基化。我们提出了一种新型的分子成像方式，它将允许在活鼠癌模型中进行聚糖的空间时间行为。这样的工具将推进糖生物学领域，加快对新疾病生物标志物的发现和验证，并使用高级生物学疾病模型桥接传统的生物化学。除了基本的癌症生物学前景之外，成像肿瘤Glyce还可以表明肿瘤侵袭性。这些信息将指导诸如前列腺癌（前列腺切除术与“主动监测”）以及其他癌症类型的疾病的治疗决策。我们将优化一种基于光学相干断层扫描的新成像仪器，以允许在具有超高灵敏度的生物组织中可视化基于纳米颗粒的对比剂（AIM 1）。其次，我们将合成两种新类的纳米颗粒成像剂：第一个用于靶向和可视化特定的聚糖发作（AIM 2A），第二个用于靶向和可视化特定蛋白质的特定聚糖发作（AIM 2B）。第一类成像剂将用于可视化唾液酸的水平，唾液酸水平是与癌症进展和转移相关的重要聚糖。第二类将用于监测€3整联蛋白上的唾液酸水平。 €3整联蛋白的溶解作用可能在促进血管生成和转移中起着至关重要的作用，但目前知之甚少。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的时空模式和前列腺癌进展过程中的整合蛋白的时空模式（AIM 3）。 公共卫生相关性：我们旨在开发下一代医学成像技术，这些技术将允许在前列腺癌进展过程中观察内部器官并收集有关哪些分子被激活的信息。这种成像技术可能会提供对癌症发展的新基本理解，也可以为临床工具提供帮助，以帮助早期发现和更好地治疗癌症患者。通过对前列腺癌中的某些糖分子进行成像，我们旨在确定肿瘤侵袭性，并提供临床见解，以决定进行前列腺切除术与“主动监测”。