Mechanism of angiogenin-induced angiogenesis

血管生成素诱导血管生成的机制

• 批准号: 8307301
• 负责人: GUO-FU HU
• 金额: $ 26.8万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307301
• 关键词: Address; Amino Acids; Amyotrophic Lateral Sclerosis; Animal Model; Animals; Antibodies; Antineoplastic Agents; Apoptosis; Binding; Binding Sites; Biological; Biological Process; Cell Death; Cell Nucleolus; Cell Nucleus; Cell Proliferation; Cell Surface Receptors; Cell Survival; Cells; Code; Cytoplasmic Granules; Cytoskeleton; Destinations; Embryo; Endocytosis; Fibroblasts; Funding; Genes; Genetic; Genetic Transcription; Goals; Growth; Human; Internal Ribosome Entry Site; Knock-out; Knockout Mice; Legal patent; Ligands; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Mediating; Messenger RNA; Molecular Target; Monoclonal Antibodies; Mus; Neomycin; Nerve Degeneration; Neurodegenerative Disorders; Nuclear Translocation; Nude Mice; Oncogenic; Paper; Patients; Peptides; Phosphorylation; Play; Predisposition; Production; Promoter Regions; Prostate; Protein Array Analysis; Proteins; Proto-Oncogene Proteins c-akt; Receptor Signaling; Ribonucleases; Ribosomal DNA; Ribosomal RNA; Role; Semaphorins; Signal Pathway; Signal Transduction; Small Interfering RNA; Small RNA; Stress; Testing; Therapeutic; Transcription Process; Transfer RNA; Transgenic Animals; Transgenic Mice; Transgenic Organisms; Translations; Tumor Angiogenesis; Work; Xenograft procedure; angiogenesis; angiogenin; angiogenin receptor; autocrine; biological adaptation to stress; cancer cell; cell growth; chemical carcinogen; drug development; inhibiting antibody; inhibitor/antagonist; intraepithelial; knock-down; loss of function mutation; novel; overexpression; paracrine; research study; response; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Angiogenin (ANG) is a 14 kDa angiogenic ribonuclease that is upregulated in a variety of human cancers. Loss-of-function mutations in the coding region of ANG have recently been found in patients with amyotrophic lateral sclerosis (ALS). Studies carried out in the previous funding period have demonstrated an important role of ANG in ribosomal RNA (rRNA) synthesis, which is essential for many fundamental biological processes including cell growth, proliferation, and survival. We have created conditional Ang1 knockout mice and have shown that Ang1 null mice have reduced angiogenic response and increased susceptibility to stress-induced apoptosis. Mechanistically, we have demonstrated that the biological activity of ANG relies on its subcellular destination. Under growth condition, ANG is translocated to the nucleus where it stimulates ribosomal RNA (rRNA) transcription and processing thereby promoting cell growth and proliferation. Under stress, ANG is translocated to the stress granules where it enhances the production of tiRNA (tRNA-derived, stress-induced small RNA) that reprogram protein translation thereby promoting cell survival. We have also identified PlexinB2 as a functional ANG receptor that is both necessary and sufficient for mediating biological activity of ANG. We have shown that ANG and Semaphorin 4C (Sema4C), the other ligand of PlexinB2, bind at non-overlapping regions and trigger different signals. The objective of this proposal is to understand the mechanism of action of ANG in stimulating angiogenesis and cancer progression. This objective will be achieved by addressing the following four specific aims. (1) Assess the therapeutic activity of anti-ANG receptor (PlexinB2) antibody. We will examine the effect of anti-PlexinB2 monoclonal antibodies on angiogenesis and tumor progression in both xenograft and transgenic animal models. (2) Characterize the differential effect of ANG and Sema4C in angiogenesis and tumor progression. We will assess the effect of knockdown PlexinB2 and Sema4C on Akt- induced prostate intraepithelial (PIN) and compare the results with that from ANG knockdown. (3) Determine the role of ANG in stress-regulated protein translation and cell survival. We will identify the signals that direct translocation of ANG into stress granules and into nucleus. We will also characterize the role of ANG-mediated tiRNA in reprogramming protein translation and promoting cell survival. (4) Characterize the effect of Ang1 knockout and ANG overexpression in angiogenesis and tumor growth. We will examine the function of ANG in cancer susceptibility to oncogenic insults inflicted by environmental and genetic factors. We will also study autocrine vs. paracrine action of ANG and their respective contributions toward tumor angiogenesis and cancer cell proliferation. We anticipate that the results of these experiments will elucidate how ANG interacts with its cell surface receptor, how the signaling pathway is transduced, and how ANG promotes cell survival and proliferation. These results will provide a comprehensive understanding of the function and mechanism of ANG in angiogenesis and in cancer progression.

描述(申请人提供)：血管生成素(Ang)是一种14 kDa的血管生成核糖核酸酶，在多种人类癌症中上调。最近在肌萎缩侧索硬化症(ALS)患者中发现了Ang编码区的功能丧失突变。在之前的资助时期进行的研究表明，血管紧张素转换酶在核糖体RNA(RRNA)合成中发挥着重要作用，核糖体RNA合成是细胞生长、增殖和生存等许多基本生物学过程所必需的。我们已经创建了条件性Ang1基因敲除小鼠，并表明Ang1基因缺失的小鼠血管生成反应减少，对应激诱导的细胞凋亡的敏感性增加。从机制上讲，我们已经证明血管紧张素转换酶的生物活性依赖于它的亚细胞目的地。在生长条件下，Ang被转移到细胞核，在那里它刺激核糖体RNA(RRNA)的转录和加工，从而促进细胞的生长和增殖。在压力下，Ang被转移到应激颗粒，在那里它增强了tiRNA(tRNA衍生的，应激诱导的小RNA)的产生，从而重新编程蛋白质翻译，从而促进细胞存活。我们还鉴定了PlexinB2是一种功能性的Ang受体，它是介导Ang生物学活性的必要条件和充分条件。我们已经证明Ang和PlexinB2的另一个配体Semaphorin 4C(Sema4C)结合在不重叠的区域并触发不同的信号。本研究的目的是了解血管紧张素转换酶在促进血管生成和肿瘤进展中的作用机制。这一目标将通过处理以下四个具体目标来实现。(1)评价抗Ang受体(PlexinB2)抗体的治疗活性。我们将在异种移植和转基因动物模型中检测抗PlexinB2单抗对血管生成和肿瘤进展的影响。(2)研究Ang和Sema4C在血管生成和肿瘤进展中的不同作用。我们将评估基因敲除PlexinB2和Sema4C对Akt诱导的前列腺上皮内(PIN)的影响，并将结果与Ang基因敲除的结果进行比较。(3)确定Ang在应激调节蛋白翻译和细胞存活中的作用。我们将确定将Ang转位到应激颗粒和细胞核的信号。我们还将描述Ang介导的tiRNA在重新编程蛋白质翻译和促进细胞存活方面的作用。(4)研究血管紧张素转换酶基因敲除和血管紧张素转换酶过表达在血管生成和肿瘤生长中的作用。我们将研究血管紧张素转换酶在癌症对环境和遗传因素造成的致癌伤害的易感性中的作用。我们还将研究Ang的自分泌和旁分泌作用，以及它们在肿瘤血管生成和癌细胞增殖中的各自作用。我们预计，这些实验的结果将阐明Ang如何与其细胞表面受体相互作用，如何转导信号通路，以及Ang如何促进细胞存活和增殖。这些结果将有助于全面了解Ang在血管生成和肿瘤进展中的作用和机制。