Decoy Receptors in Lymphangiogenesis

淋巴管生成中的诱饵受体

• 批准号: 8686614
• 负责人: Klara Rachel Klein
• 金额: $ 3.34万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8686614
• 关键词: Affect; Amino Acids; Area; Binding; Biological Assay; Blood Vessels; Bromodeoxyuridine; Cell Proliferation; Chronic; Data; Defect; Development; Disease Progression; Edema; Embryo; Exhibits; Fatty acid glycerol esters; G-Protein-Coupled Receptors; Genetic; Glean; Grant; Growth; Hyperplasia; Immunoblotting; Immunologic Surveillance; In Situ; In Vitro; Inflammation; Knockout Mice; Knowledge; Literature; Lymph; Lymphangiogenesis; Lymphatic; Lymphatic Diseases; Lymphatic Endothelial Cells; Lymphatic System; Lymphatic vessel; Lymphedema; MAP Kinase Gene; Measures; Mediating; Modern Medicine; Molecular; Mus; Neoplasm Metastasis; Peptides; Phenotype; Prevalence; Process; Proteins; Regulation; Resolution; Role; Signal Transduction; Skin; Small Interfering RNA; Stromal Cell-Derived Factor 1; Swelling; Systems Development; Testing; Tissues; Vascular Diseases; absorption; adrenomedullin; adrenomedullin receptor; base; calcitonin receptor-like receptor; dosage; gain of function; in vitro Model; in vivo; insight; interstitial; loss of function; mouse model; new therapeutic target; novel; overexpression; public health relevance; receptor; receptor-activity-modifying protein; research study; response; tumor; tumor microenvironment; wound

DESCRIPTION (provided by applicant): The lymphatic vasculature has been implicated in a variety of pathophysiological processes, including tumor metastasis, tissue inflammation, edema, impaired immune surveillance and disrupted fat absorption. Nevertheless, it is remarkable that modern medicine has yet to discover pharmacologically-tractable targets for the modulation of lymphatic vessel growth or function; largely because the molecular mechanisms that control lymphangiogenesis remain poorly understood. Our lab has shown that adrenomedullin (AM), a 52-amino acid peptide that is secreted by lymphatic endothelial cells (LECs), is essential for proper embryonic lymphatic vascular development and that fine-tuned control of AM dosage is critical for the regulation of both embryonic and pathological lymphangiogenesis. CXCR7 was originally identified as an AM receptor, but has more recently been studied for its functions as a decoy receptor for SDF-1. Our preliminary studies suggest that CXCR7 is expressed in developing LECs and that CXCR7-/- mice exhibit lymphatic phenotypes consistent with AM overexpression. Therefore, I propose to investigate the hypothesis that CXCR7 serves as a decoy receptor for AM which consequently provides fine-tuned control of AM-mediated proliferation of LECs. I will perform comprehensive phenotypic analysis of lymphangiogenesis in loss-of-function CXCR7-/- mice in order to define the role of CXCR7 during in vivo lymphangiogenesis. In addition, I propose to cross CXCR7-/- mice to mice that are haploinsufficient for AM in order test whether the decoy activity of CXCR7 is required for the control of AM- mediated lymphangiogenesis in vivo. I will also use both loss-of-function and gain-of-function in vitro models to elucidate whether CXCR7 dampens AM-mediated downstream signaling. LECs will be cultured and treated with AM for proliferation assays, immunoblot, and 3D spheroid sprouting assays to explore the role of CXCR7 on AM-mediated LEC proliferation, downstream signaling, and mature vessel formation. Results from this proposal will define the role of CXCR7 in AM signaling and lymphangiogenesis and may elucidate novel therapeutic targets for the treatment of poorly managed lymphatic vascular diseases.

描述（由申请方提供）：淋巴管系统参与了多种病理生理过程，包括肿瘤转移、组织炎症、水肿、免疫监视受损和脂肪吸收中断。然而，值得注意的是，现代医学尚未发现用于调节淋巴管生长或功能的药理学上易处理的靶点;主要是因为控制淋巴管生成的分子机制仍然知之甚少。我们的实验室已经表明，肾上腺髓质素（AM），由淋巴管内皮细胞（LEC）分泌的52个氨基酸的肽，是必要的适当的胚胎淋巴管血管发育和微调控制AM剂量是至关重要的胚胎和病理淋巴管生成的调节。CXCR 7最初被鉴定为AM受体，但最近研究了其作为SDF-1诱饵受体的功能。我们的初步研究表明，CXCR 7在发展中的LEC中表达，CXCR 7-/-小鼠表现出与AM过表达一致的淋巴表型。因此，我建议调查的假设，CXCR 7作为一个诱饵受体AM，从而提供了微调控制AM介导的LEC增殖。我将对功能丧失的CXCR 7-/-小鼠的淋巴管生成进行全面的表型分析，以确定CXCR 7在体内淋巴管生成过程中的作用。此外，我建议将CXCR 7-/-小鼠与AM单倍不足的小鼠杂交，以测试CXCR 7的诱饵活性是否是控制AM介导的体内淋巴管生成所必需的。我还将使用功能丧失和功能获得的体外模型来阐明CXCR 7是否抑制AM介导的下游信号传导。将培养LEC并用AM处理，用于增殖测定、免疫印迹和3D球状体发芽测定，以探索CXCR 7对AM介导的LEC增殖、下游信号传导和成熟血管形成的作用。该提案的结果将确定CXCR 7在AM信号传导和淋巴管生成中的作用，并可能阐明治疗管理不善的淋巴管疾病的新治疗靶点。