Notch Signaling in Mouse Arterial-Venous Specification

小鼠动静脉规范中的 Notch 信号转导

• 批准号: 7209043
• 负责人: Rong Wang
• 金额: $ 35.91万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7209043
• 关键词: Adult; Angioblast; Aorta; Arteries; Arteriogram; Biological; Biological Markers; Blood Circulation; Blood Vessels; Blood flow; Candidate Disease Gene; Cardinal vein; Cell Adhesion; Cell Communication; Cell Proliferation; Cell Separation; Cell Survival; Cells; Cessation of life; Complex; Condition; Defect; Development; Dissection; Dorsal; Down-Regulation; Drug Delivery Systems; Embryo; Endothelial Cells; Endothelium; EphB4 Receptor; Equilibrium; Event; Feedback; Future; Gene Expression; Genes; Genetic; Goals; Image; Investigation; Knockout Mice; Lead; Lesion; Link; Liver; Lung; Maintenance; Methods; Modeling; Molecular; Molecular Probes; Morphogenesis; Mus; Pathogenesis; Pathway interactions; Pattern; Phenotype; Process; Regulation; Research Personnel; Role; Seminal; Signal Transduction; Smooth Muscle Myocytes; Specific qualifier value; Staging; Techniques; Testing; Tetanus Helper Peptide; Tetracycline; Tetracyclines; Therapeutic Intervention; Time; Transgenes; Transgenic Mice; Up-Regulation; Vascular Diseases; Veins; Venous; Work; Yolk Sac; Zebrafish; cell type; embryo culture; gene function; interest; loss of function; member; mouse model; mutant; notch protein; novel; postnatal; prenatal; pressure; programs; research study; transgene expression

DESCRIPTION (provided by applicant): Our long-term goal is to ascertain the molecular mechanisms responsible for the normal development and maintenance of the mammalian vasculature and to elucidate molecular lesions underlying vascular pathogenesis. Recent experiments performed on zebrafish have suggested that Notch expression provokes arterial development while its down-regulation results in the default development of veins. Despite these findings in zebrafish, mouse knockout experiments suggest Notch's role in mammilian arterial-venous (AV) development is more complex. Furthermore, the precise cellular and molecular events remain to be defined. To determine the function of the Notch pathway in AV differentiation both in mouse embryos and adults, our lab has developed a mouse model, in which a constituitively active form of Notch is expressed exclusively in endothelial cells. Furthermore, the activated Notch expression is temporally regulatable, thereby allowing us to examine its effects in both developmental and adult vasculature. Using this and other Notch mutants, we will accomplish the following specific aims: define the role of Notch in embryonic AV differentiation (Aim 1); define the role of Notch in adult maintenance of AV identity (Aim 2); define the cellular mechanisms by which Notch specifies differentiation of arteries and veins (Aim 3); and identify the molecular events triggered by Notch in endothelial cells (Aim 4). The specific aims of this study, engaging morphological, cellular, and molecular analyses, entail both gain-and loss-of-function studies of Notch in endothelial cells. These efforts will reveal the role of Notch in vascular differentiation and maintenance and illuminate potential molecular mechanisms underlying these processes. In the future, this basic understanding of Notch in pre and postnatal mammalian vascular function will guide investigations into its function under pathological conditions, such as ischemic collateral artery formation. Ultimately, our understanding of the Notch pathway may lead to the identification of novel drug targets and therapeutic interventions to vascular diseases.

描述（由申请人提供）：我们的长期目标是确定负责哺乳动物血管系统正常发育和维持的分子机制，并阐明血管发病机制下的分子病变。最近在斑马鱼上进行的实验表明，Notch表达引起动脉发育，而其下调导致静脉的默认发育。尽管在斑马鱼中有这些发现，但小鼠敲除实验表明Notch在乳头状动脉-静脉（AV）发育中的作用更为复杂。此外，精确的细胞和分子事件仍有待确定。为了确定Notch通路在小鼠胚胎和成年人AV分化中的功能，我们的实验室开发了一种小鼠模型，其中Notch的组成型活性形式仅在内皮细胞中表达。此外，激活的Notch表达是暂时可调节的，从而使我们能够检查其在发育和成人血管系统中的作用。使用该突变体和其他Notch突变体，我们将实现以下特定目标：确定Notch在胚胎AV分化中的作用（目标1）;确定Notch在成人AV身份维持中的作用（目标2）;确定Notch指定动脉和静脉分化的细胞机制（目标3）;以及确定Notch在内皮细胞中触发的分子事件（目标4）。这项研究的具体目的，从事形态学，细胞和分子分析，需要在内皮细胞中的Notch功能的获得和丧失的研究。这些努力将揭示Notch在血管分化和维持中的作用，并阐明这些过程的潜在分子机制。在未来，这种对Notch在出生前和出生后哺乳动物血管功能中的基本理解将指导其在病理条件下的功能研究，例如缺血性侧支动脉形成。最终，我们对Notch通路的理解可能会导致识别新的药物靶点和血管疾病的治疗干预。