Elucidating the GPCR protein networks that drive lymphatic growth

阐明驱动淋巴生长的 GPCR 蛋白网络

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要：淋巴病很多，影响了2亿以上的人全世界。这些慢性疾病的临床管理有限，并且广泛地以异常为特征淋巴血管发育和/或功能障碍，导致间质液的疼痛积累。令人震惊的是，没有针对FDA批准的药理学靶向淋巴管生成，这是淋巴管形成，可用。因此，迫切需要对钥匙进行治疗表征调节淋巴管生成的可疗法蛋白质和信号通路。卡伦实验室研究一这样的分子，有效的促淋巴管肽，肾上腺肾上腺素（AM）。 AM诱导的淋巴管生成需要形成良好控制的AM-化学梯度，以提供增长和迁移的方向性淋巴管尖端。非典型的趋化因子受体3（ACKR3）对于建立它们至关重要通过AM的内在化和降解梯度。最近，卡伦实验室确定了一本小说 ACKR3与受体活性修饰蛋白3之间的相互作用（RAMP3）。他们在体外表明刺激的内在化和 ACKR3或RAMP3体内的损失导致血管发育受损。但是，通过 RAMP3调节淋巴内皮细胞（LEC）中的ACKR3活性和信号传导以及淋巴管生成仍然未知。 RAMP3在坡道中是唯一的，因为它包含C端PDZ 通过促进蛋白质 - 蛋白质与含PDZ结构域的蛋白质相互作用来介导其功能的基序。因此，该培训建议的总体假设是RAMP3及其PDZ主题增强 ACKR3活性和LEC内的信号传导调节淋巴管生成。该提案的完成将定义 RAMP3在调节ACKR3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，该建议将提供宝贵的经验和培训在道德和严格的研究以及有效的科学沟通的表现中。