Elucidating the GPCR protein networks that drive lymphatic growth

项目摘要/摘要：淋巴疾病数不胜数，影响超过2亿人 全世界。这些慢性疾病的临床治疗有限，其主要特征是异常。 淋巴管发育和/或功能障碍，导致疼痛的间质积液。 令人震惊的是，没有FDA批准的针对淋巴管生成的药物治疗，其过程 淋巴管形成，是可用的。因此，迫切需要对关键的治疗方法进行表征。 调节淋巴管生成的易处理的蛋白质和信号通路。卡隆实验室研究了一项 这种分子，强大的促淋巴管生成多肽，肾上腺髓质素(AM)。AM诱导的淋巴管生成 需要形成控制良好的AM-趋化梯度，以提供生长和迁移的方向性 淋巴管末端。非典型趋化因子受体3(ACKR3)对这些细胞的建立至关重要 AM内化和降解过程中的梯度最近，卡隆实验室发现了一种新的 ACKR3与受体活性修饰蛋白3(RAMP3)的相互作用他们在体外表明， RAMP3是AM刺激内化后ACKR3循环到质膜上所必需的，并且 体内ACKR3或RAMP3的缺失会导致血管发育受损。然而，这一机制通过 哪个RAMP3调节淋巴内皮细胞的ACKR3活性和信号转导，以及 淋巴管生成仍不清楚。RAMP3在斜坡中是独一无二的，因为它包含一个C端子PDZ 通过促进蛋白质与含有PDZ结构域的蛋白质相互作用来调节其功能的基序。 因此，该训练方案的首要假设是RAMP3及其PDZ基序增强 ACKR3活性和信号在LECs内调节淋巴管生成。本提案的完成将定义 RAMP3在调节ACKR3信号和淋巴管生成中的作用，从而促进电流 淋巴生物学领域的知识。此外，这项提议将提供宝贵的经验和培训。 在伦理和严谨的研究和有效的科学交流方面表现出色。

Project Summary/ Abstract: Lymphatic diseases are numerous and affects upwards of 200 million people worldwide. These chronic disorders have limited clinical management and are broadly characterized by aberrant lymphatic vessel development and/or dysfunction which results in painful accumulation of interstitial fluid. Shockingly, no FDA-approved pharmacological treatments targeting lymphangiogenesis, the process of lymphatic vessel formation, are available. Thus, there is an urgent need to characterize key therapeutically tractable proteins and signaling pathways that regulate lymphangiogenesis. The Caron laboratory studies one such molecule, the potent pro-lymphangiogenic peptide, adrenomedullin (AM). AM-induced lymphangiogenesis requires formation of well-controlled AM-chemotactic gradients to provide directionality to growing and migrating lymphatic vessel tips. The atypical chemokine receptor 3 (ACKR3) is critical for the establishment of these gradients through the internalization and degradation of AM. Recently, the Caron laboratory identified a novel interaction between ACKR3 and receptor-activity-modifying protein 3 (RAMP3). They showed in vitro that RAMP3 is required for the recycling of ACKR3 to the plasma membrane after AM-stimulated internalization and that loss of ACKR3 or RAMP3 in vivo results in impaired vascular development. However, the mechanism by which RAMP3 regulates ACKR3 activity and signaling in lymphatic endothelial cells (LECs) and the process of lymphangiogenesis remains unknown. RAMP3 is unique among the RAMPs in that it contains a C-terminal PDZ motif that mediates its function by promoting protein-protein interactions with PDZ domain-containing proteins. Therefore, the overarching hypothesis of this training proposal is that RAMP3 and its PDZ motif enhances ACKR3 activity and signaling within LECs to regulate lymphangiogenesis. Completion of this proposal will define the role of RAMP3 in the regulation of ACKR3 signaling and lymphangiogenesis, thereby advancing the current knowledge of the lymphatic biology field. In addition, this proposal will provide invaluable experience and training in the performance of ethical and rigorous research and effective scientific communication.