Adrenomedullin Signaling in Vascular Development

血管发育中的肾上腺髓质素信号传导

• 批准号: 7586097
• 负责人: Kathleen M Caron
• 金额: $ 36.1万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7586097
• 关键词: Amino Acids; Angiogenic Peptides; Animals; Area; Binding; Biological Assay; Blood; Blood Vessels; Cardiovascular system; Cell Proliferation; Cells; Corneal Neovascularization; Defect; Development; Edema; Embryo; Embryonic Development; Endothelial Cells; Engineering; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Gene Dosage; Gene Targeting; Genes; Genetic; Genetically Engineered Mouse; Genomics; Hydrops Fetalis; Hypertension; Knockout Mice; Laboratories; Ligand Binding; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphedema; MAP Kinase Gene; Mediating; Mediator of activation protein; Migraine; Mus; Myocardial Infarction; NIH Program Announcements; Neoplasm Metastasis; Pathway interactions; Peptides; Permeability; Phenotype; Pregnancy; Process; Proteins; RAMP2; Series; Signal Transduction; Specificity; System; Tail; Technology; Testing; Transcriptional Regulation; Transgenic Mice; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vasodilator Agents; adrenomedullin; adrenomedullin receptor; anasarca; angiogenesis; base; calcitonin receptor-like receptor; dosage; in vivo; insight; interest; meetings; mouse model; novel; postnatal; public health relevance; receptor; receptor-activity-modifying protein; spatiotemporal; tumor

DESCRIPTION (provided by applicant): The angiogenic peptide vasodilator adrenomedullin (AM) signals through a G-protein coupled receptor (GPCR) called calcitonin receptor-like receptor (CLR) when the receptor is bound to a novel class of proteins called receptor activity modifying proteins (RAMPs). Using genetically engineered mouse models lacking each of the components of AM signaling, we have consistently identified a rare type of embryonic lethality that is characterized by generalized edema caused by defects in lymphangiogenesis. We hypothesize that AM signaling in endothelial cells is an essential mediator of lymphangiogenesis during embryonic development. Our long-term objective, to define the function of AM signaling during lymphatic vascular development can be met in the following aims: Specific Aim 1 is geared toward determining the cellular origin of the lymphatic vascular defects and the dosage of AM signaling required for normal lymphangiogenesis. We will generate and characterize novel genetic mouse models to elucidate i) if AM signaling in endothelial cells is necessary for normal lymphangiogenesis ii) if AM signaling in endothelial cells is sufficient to support normal lymphangiogenesis and iii) the minimum dosage of AM required for normal lymphangiogenesis. Specific Aim 2 will test the hypothesis that AM is a potent modulator of lymphatic endothelial cell proliferation and permeability due to preferential expression of its receptors in lymphatic versus blood endothelial cells. Results from this aim will distinguish genotypic and phenotypic differences between lymphatic and blood vascular cells and will provide a mechanistic basis for the underlying cause of hydrops in the null mouse models. In Specific Aim 3, we plan to identify genetic pathways that interact with the AM Signaling System to modulate its functions either in healthy or edematous lymphatic vasculature. The functional significance of positively identified pathways will be confirmed through an embryoid body culture system, in vivo corneal neovascularization assays and tail microlymphography. Results from this aim will define the functional consequences of altered AM activity in the lymphatic vasculature and will elucidate how this pathway interacts with other pathways to mediate lymphangiogenesis. By completing these aims we hope to provide novel insights into the processes that govern lymphangiogenesis during development and thus identify a new class of protein targets which can modulate the lymphatic vasculature for the treatment of conditions such as lymphedema or the inhibition of tumor metastasis. PUBLIC HEALTH RELEVANCE We have demonstrated that genes required for mediating the signal of a potent angiogenic peptide, adrenomedullin, are required for lymphangiogenesis during embryonic development. We plan to elucidate the functions of AM signaling in the lymphatic vasculature. In doing so, we hope to provide novel insights into the processes that govern lymphangiogenesis during development and thus identify a new class of protein targets which can modulate the lymphatic vasculature for the treatment of conditions such as lymphedema or the inhibition of tumor metastasis.

描述（由申请人提供）：通过G蛋白偶联受体（GPCR）信号（称为降钙素受体受体受体样受体（CLR））当受体与新型蛋白质的受体活性修饰蛋白（RAMPS）结合时，被称为降钙素受体受体受体（CLR）的血管生成肽血管扩张蛋白（AM）信号。使用缺乏AM信号传导组件的基因工程的小鼠模型，我们始终识别出一种罕见的胚胎致死性，该胚胎的杀伤力是由淋巴管生成中缺陷引起的普遍水肿的特征。我们假设内皮细胞中的AM信号传导是胚胎发育过程中淋巴管生成的重要介质。在以下目的中可以满足我们的长期目标，以确定淋巴血管发育过程中AM信号传导的功能：特定目标1旨在确定淋巴血管缺陷的细胞起源，以及正常淋巴管生成所需的AM信号传导剂量。我们将生成并表征新型的遗传小鼠模型以阐明i）i）如果内皮细胞中的AM信号传导对于正常淋巴管生成是必要的ii）如果内皮细胞中的AM信号足以支持正常的淋巴管生成并且III）iii）AM所需的AM最小剂量对于正常淋巴管生成。具体目标2将检验AM是淋巴内皮细胞增殖的有效调节剂和由于其受体在淋巴和血液内皮细胞中的优先表达而引起的渗透率。该目标的结果将区分淋巴和血管细胞之间的基因型和表型差异，并将为NULL小鼠模型中的水力基本原因提供机械基础。在特定目标3中，我们计划鉴定与AM信号系统相互作用的遗传途径，以调节其在健康或大肿瘤淋巴管中的功能。正面鉴定的途径的功能意义将通过胚胎体培养系统，体内角膜新生血管化测定和尾部微检查者确认。该目标的结果将定义淋巴脉管系统中AM活性改变的功能后果，并将阐明该途径如何与其他途径相互作用以介导淋巴管生成。通过完成这些目标，我们希望为在发育过程中淋巴管生成的过程提供新的见解，从而确定一类新的蛋白质靶标，这些蛋白质靶标可以调节淋巴管脉管系统，以治疗淋巴水肿或抑制肿瘤转移的疾病。 公共卫生相关性我们已经证明，介导有效的血管生成肽肾上腺素的信号所需的基因是胚胎发育过程中淋巴管生成所必需的。我们计划阐明AM信号传导在淋巴管系统中的功能。在此过程中，我们希望对在发育过程中淋巴管生成的过程提供新的见解，从而确定一类新的蛋白质靶标，这些蛋白质靶标可以调节淋巴管脉管系统，以治疗淋巴水肿或肿瘤转移的抑制。