Molecular Targeting of Lymphatic Endothelial Receptors for Ligand-directed Imagin

淋巴血管系统在许多疾病的发病机制中起着至关重要的作用，包括炎症性疾病、淋巴水肿、肿瘤进展和转移。最近，淋巴管在肿瘤传播和转移等疾病状态中的重要作用已被认识到，肿瘤相关淋巴管的数量与淋巴结转移有关。从蛋白质表达水平及其调节功能方面发现和表征淋巴管微环境将有助于揭示淋巴管在这些疾病状态（淋巴水肿、淋巴管瘤、组织修复、炎症和银屑病皮损）中发挥的特定作用。我们在体内选择系统方面有丰富的经验，其中在静脉注射噬菌体（噬菌体）随机肽库后，选择性地回到不同组织的肽被恢复。在这里，我们建议调整这一选择过程，并对前哨淋巴结作图和淋巴结活检过程中切除的淋巴管进行体外噬菌体筛选。我们还可以采用几种基于噬菌体展示的方法来定义淋巴通道中存在的细胞和分子差异。这些筛选将揭示淋巴靶向肽，这将最终导致受体鉴定，并提供更完整的淋巴内皮分子图谱和配体定向成像的基础。我们还预计，这里确定的靶向配体可能有助于开发新的策略，以了解/预防转移和靶向成像，以监测疾病的进展，如淋巴水肿。我们的具体目标是：(i)分离淋巴管归巢肽并鉴定相应的淋巴细胞表面受体；（ii）评估淋巴管受体归巢能力，用于设计靶向分子成像。我们假设淋巴管之间的分子地址可以用于基于配体的功能性和/或病变淋巴管成像。

The lymphatic vasculature plays a critical role in the pathogenesis of many diseases including inflammatory disorders, lymphedema, tumor progression, and metastasis. More recently, the important role of lymphatic vessels in disease states such as tumor dissemination and metastasis has been recognized with the correlation of the number of tumor-associated lymphatic vessels with lymph node metastasis. Discovery and characterization of the lymphatic vessel microenvironment in terms of protein expression levels and their regulatory function will help unravel the specific role lymphatic vessels play in these disease states among others (lymphedema, lymphangioma, tissue repair, inflammation, and psoriatic skin lesions). We have extensive experience with the in vivo selection system in which peptides that home selectively to different tissues are recovered after intravenous administration of a bacteriophage (phage) random peptide library. Here we propose to adapt this selection process and perform an ex vivo phage screening on lymphatic vessels removed during sentinel lymphatic mapping and lymph node biopsy procedures. We may additionally employ several phage display-based approaches to define the cellular and molecular differences that exist in lymphatic channels. These screenings will unveil lymphatic targeting peptides, which will ultimately lead to receptor identification and provide a more complete molecular profile of the lymphatic endothelium and a basis for ligand-directed imaging. We also anticipate that the targeted ligands identified here may be useful in the development of new strategies in the understanding/prevention of metastasis and targeted imaging to monitor the progression of diseases, such as lymphedema. Our Specific Aims are: (i) To isolate lymphatic vessel homing peptides and identify the corresponding lymphatic cell surface receptors and (ii) To evaluate the lymphatic receptor homing capabilities for the design of targeted molecular imaging. We hypothesize that molecular addresses among lymphatic vessels can be exploited for ligand-based imaging of functional and/or diseased lymphatic vessels.