Targeting Lymphatic Vessels for Ligand Directed Imaging

靶向淋巴管进行配体定向成像

• 批准号: 9234681
• 负责人: WADIH ARAP
• 金额: $ 34.66万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234681
• 关键词: Address; Antibodies; Bacteriophages; Base Sequence; Binding; Biochemical; Bioinformatics; Biological; Biological Markers; Blood Vessels; Cell Cycle Regulation; Cell Proliferation; Cell Surface Receptors; Cell surface; Cells; Cessation of life; Clinical; Code; Conceptions; Development; Disease; Disease Progression; Endothelial Cells; Endothelium; Excision; Foundations; Future; Generations; Goals; Home environment; Homing; Human; Image; In Vitro; Kinetics; Label; Laboratories; Lead; Libraries; Ligand Binding; Ligands; Literature; Lymphatic; Lymphatic Endothelial Cells; Lymphatic Endothelium; Lymphatic System; Lymphatic vessel; Malignant Neoplasms; Maps; Mediating; Melanoma Cell; Membrane Proteins; Microscopy; Molecular; Molecular Profiling; Neoplasm Metastasis; Ontology; Operative Surgical Procedures; Organ; Paper; Patients; Pattern; Peptide Library; Peptides; Phage Display; Phosphoric Monoester Hydrolases; Procedures; Property; Protein Isoforms; Protein Serine/Threonine Phosphatase; Protein phosphatase; Proteins; Proteomics; Resected; Role; Sampling; Sentinel Lymph Node Biopsy; Signal Transduction; Site; Surface; Syndrome; System; Technology; Time; Tissues; Validation; Work; antibody libraries; base; combinatorial; data mining; design; experimental study; extracellular; fascinate; human disease; imaging agent; imaging platform; imaging system; in vivo; innovation; insight; melanoma; molecular imaging; molecular marker; new therapeutic target; non-invasive imaging; novel; novel strategies; practical application; prognostic; protein expression; protein protein interaction; receptor; scaffold; screening; selective expression; statistics; targeted agent; targeted imaging; targeted treatment; tool; translational diagnostics; trend; vascular bed

ABSTRACT . In particular, the The phenomenon of molecular changes to the lymphatic endothelial cells and the biological role(s) of the lymphatic vasculature in the metastatic cascade of human cancer are not entirely understood syndrome of in-transit melanoma is a fascinating clinical example of disease presentation in search of a pathophysiological basis. In our recent paper, Ligand-directed targeting of lymphatic vessels uncovers mechanistic insights in melanoma metastasis (Christianson et al. PNAS, 2015), we performed ex vivo combinatorial screens using random peptide phage libraries of draining lymphatic channels removed directly from patients during melanoma excision surgeries. We discovered a functional ligand-receptor system by selecting, isolating, and validating a new homophilic protein-protein interaction between malignant melanoma cells and lymphatic endothelial cells. This unique and previously unrecognized finding provides the foundation for the development and optimization of a new platform for ligand-directed imaging of the lymphatic system. Here, we propose to interrogate previously identified peptide ligands that bind to the surface of the lymphatic endothelium during disease progression to develop a novel, ligand-directed, non-invasive in vivo lymphatic imaging platform. Specifically, our goals are to: (1) Use innovative chem- and bio-informatics data mining systems to define the ontology of enriched lymphatic vessel homing peptides, (2) Investigate the binding properties of selected peptide ligands and their corresponding receptors in vitro, and (3) Develop and implement targeted imaging systems to study the lymphatic endothelium. Peptides that home to PPP2R1A, a new powerful lymphatic marker, will be prioritized. Our long-term goal, subsequent to the completion of the work proposed here, is to discover new lymphatic biomarkers associated with disease progression and generate a panel of ligand-based imaging agents that specifically target the surface of the lymphatic endothelium for prognostic and diagnostic translational applications. We anticipate that the newly characterized lymphatic molecular addresses and validated, corresponding ligands and antibodies will be of great value for the development of targeted agents, establishing for the first time, a platform for non-invasive imaging of the lymphatic system, and, in the future, contribute to our understanding of the role by the lymphatic vasculature in human disease.

抽象的 。特别是 分子的现象变化对淋巴内皮细胞的变化和生物学作用 人类癌症转移性级联中的淋巴脉管系统尚不完全了解 透射黑色素瘤综合征是疾病表现的一个有趣的临床例子 病理生理基础。在我们最近的论文中，配体指导的淋巴管的靶向靶向 黑色素瘤转移的机械见解（Christianson等人PNAS，2015年），我们进行了体内 使用直接去除排水淋巴通道的随机肽噬菌体库组合筛选 来自黑色素瘤切除手术期间的患者。我们通过 在恶性黑色素瘤之间选择，隔离和验证新的同质蛋白 - 蛋白质相互作用 细胞和淋巴内皮细胞。这个独特且以前未被认可的发现为基础提供了基础 为了开发和优化淋巴系统配体指导成像的新平台。 在这里，我们提议询问与淋巴表面结合的先前鉴定的肽配体 疾病进展过程中的内皮形成一种新型，配体指导的，无创的体内淋巴管 成像平台。具体而言，我们的目标是：（1）使用创新的化学和生物信息学数据挖掘 定义富集淋巴血管饲养肽本体的系统，（2）研究结合 选定肽配体及其相应受体的特性，（3）发展和 实施目标成像系统以研究淋巴内皮。 PPP2R1A的家的肽 将优先考虑新的强大淋巴标记。我们的长期目标，之后 这里提出的工作是要发现与疾病进展相关的新淋巴生物标志物 生成一组基于配体的成像剂，这些成像剂专门针对淋巴表面 用于预后和诊断翻译应用的内皮。我们预计新的特征 淋巴分子地址和经过验证，相应的配体和抗体对 目标代理的开发，首次建立，是一个非侵入性成像的平台 淋巴系统，将来，有助于我们理解淋巴管的作用 人类疾病。