Elucidating the GPCR protein networks that drive lymphatic growth

项目摘要/摘要：淋巴疾病种类繁多，影响超过2亿人 国际吧这些慢性疾病具有有限的临床管理，并且广泛地以异常的免疫应答为特征。 淋巴管发育和/或功能障碍，其导致间质液的疼痛性积聚。 令人震惊的是，没有FDA批准的针对淋巴管生成的药物治疗， 淋巴管的形成。因此，迫切需要描述关键的治疗方法， 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种 这样的分子，有效的前淋巴管生成肽，肾上腺髓质素（AM）。AM诱导的淋巴管生成 需要形成良好控制的AM-趋化梯度以提供生长和迁移的方向性 淋巴管尖端。非典型趋化因子受体3（ACKR 3）对于这些细胞的建立至关重要。 梯度通过AM的内化和降解。最近，卡隆实验室发现了一种新的 ACKR 3和受体活性修饰蛋白3（RAMP 3）之间的相互作用。他们在试管中证明， 在AM刺激的内化后，RAMP 3是ACKR 3再循环至质膜所必需的， 体内ACKR 3或RAMP 3的缺失导致血管发育受损。然而， RAMP 3调节淋巴管内皮细胞（LEC）中的ACKR 3活性和信号传导， 淋巴管生成仍然是未知的。RAMP 3在RAMP中是独特的，因为它含有C-末端PDZ 通过促进与含PDZ结构域的蛋白质的蛋白质-蛋白质相互作用来介导其功能的基序。 因此，该训练方案的总体假设是RAMP 3及其PDZ基序增强了RAMP 3的表达。 LECs内的ACKR 3活性和信号传导以调节淋巴管生成。完成本提案将定义 RAMP 3在调节ACKR 3信号传导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，这项建议将提供宝贵的经验和培训 在道德和严格的研究和有效的科学交流的性能。

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.