Elucidating the GPCR protein networks that drive lymphatic growth

阐明驱动淋巴生长的 GPCR 蛋白网络

• 批准号: 10462115
• 负责人: Donald Stephen Serafin
• 金额: $ 4.08万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462115
• 关键词: ARNT gene; Affect; Binding; Biological Assay; Biology; Biotin; Blood Vessels; C-terminal; Caliber; Cell Proliferation; Cell membrane; Cell physiology; Cells; Chronic Disease; Clinical Management; Co-Immunoprecipitations; Communication; Defect; Development; Embryo; Ethics; FDA approved; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Genetic; Growth; Harvest; Human; Immunohistochemistry; Impairment; In Vitro; Intercellular Fluid; Knowledge; Laboratories; Laboratory Study; Ligands; Lymphangiogenesis; Lymphatic; Lymphatic Diseases; Lymphatic Endothelial Cells; Lymphatic Endothelium; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Molecular Biology; Mus; N-ethylmaleimide-sensitive protein; Output; Pain; Pathologic; Patient-Focused Outcomes; Peptides; Performance; Persons; Pharmacological Treatment; Process; Proteins; Publishing; Recycling; Regulation; Reporter; Reporting; Research; Retina; Role; Signal Pathway; Signal Transduction; Techniques; Therapeutic; Training; Western Blotting; adrenomedullin; adrenomedullin receptor; cell motility; chemokine receptor; dimer; experience; improved; in vivo; innovation; interest; knock-down; lymphatic vessel; migration; mouse model; novel; overexpression; prevent; protein protein interaction; receptor; receptor function; receptor internalization; receptor-activity-modifying protein; trafficking

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.

项目概要/摘要：淋巴疾病种类繁多，影响着超过 2 亿人 全世界。这些慢性疾病的临床治疗有限，并且普遍具有异常的特征 淋巴管发育和/或功能障碍，导致间质液积聚而产生疼痛。 令人震惊的是，FDA 还没有批准针对淋巴管生成（淋巴管生成过程）的药物治疗方法。 淋巴管形成，可用。因此，迫切需要确定关键的治疗特征 调节淋巴管生成的易处理蛋白质和信号通路。卡隆实验室研究一项 这种分子，是有效的促淋巴管生成肽，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，为生长和迁移提供方向性 淋巴管提示。非典型趋化因子受体 3 (ACKR3) 对于这些机制的建立至关重要 通过 AM 的内化和降解产生梯度。最近，卡隆实验室发现了一种新颖的 ACKR3 和受体活性修饰蛋白 3 (RAMP3) 之间的相互作用。他们在体外表明 AMP3 是 AM 刺激内化后 ACKR3 循环至质膜所必需的 体内 ACKR3 或 RAMP3 的缺失会导致血管发育受损。然而，该机制通过 RAMP3 调节淋巴内皮细胞 (LEC) 中的 ACKR3 活性和信号传导及其过程 淋巴管生成仍不清楚。 RAMP3 在 RAMP 中是独一无二的，因为它包含 C 端 PDZ 通过促进与含有 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 RAMP3 及其 PDZ 基序增强了 LEC 内的 ACKR3 活性和信号传导调节淋巴管生成。该提案的完成将定义 RAMP3 在 ACKR3 信号传导和淋巴管生成的调节中的作用，从而推进了当前的研究 淋巴生物学领域的知识。此外，该提案将提供宝贵的经验和培训 进行道德和严格的研究以及有效的科学交流。