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）：当受体与一类称为受体活性修饰的新型蛋白质结合时，血管生成肽血管舒张剂肾上腺髓质素（AM）通过称为降钙素受体样受体（CLR）的G蛋白偶联受体（GPCR）发出信号蛋白质（RAMP）。使用缺乏 AM 信号传导各组成部分的基因工程小鼠模型，我们一致地鉴定出一种罕见类型的胚胎致死性，其特征是淋巴管生成缺陷引起的全身水肿。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。我们的长期目标是确定淋巴管发育过程中 AM 信号传导的功能，具体目标 1 旨在确定淋巴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遗传小鼠模型，以阐明 i) 内皮细胞中的 AM 信号传导是否是正常淋巴管生成所必需的 ii) 内皮细胞中的 AM 信号传导是否足以支持正常淋巴管生成 以及 iii) 正常淋巴管生成所需的 AM 最小剂量。具体目标 2 将检验以下假设：AM 是淋巴管内皮细胞增殖和渗透性的有效调节剂，因为与血液内皮细胞相比，AM 受体在淋巴管中优先表达。该目标的结果将区分淋巴细胞和血管细胞之间的基因型和表型差异，并将为无效小鼠模型中水肿的根本原因提供机制基础。在具体目标 3 中，我们计划确定与 AM 信号系统相互作用的遗传途径，以调节其在健康或水肿淋巴管系统中的功能。积极鉴定的途径的功能意义将通过类胚体培养系统、体内角膜新生血管化验和尾部微淋巴造影来证实。这一目标的结果将定义淋巴管系统中 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，我们希望对发育过程中控制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点，可以调节淋巴管系统，用于治疗淋巴水肿或抑制肿瘤转移等疾病。 公共健康相关性 我们已经证明，介导强效血管生成肽（肾上腺髓质素）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 信号在淋巴管系统中的功能。在此过程中，我们希望对发育过程中控制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点，可以调节淋巴管系统，以治疗淋巴水肿或抑制肿瘤转移等疾病。