Regulation of Angiogenesis by Kininogen

激肽原对血管生成的调节

基本信息

  • 批准号:
    8389601
  • 负责人:
  • 金额:
    $ 37.34万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-12-12 至 2014-11-30
  • 项目状态:
    已结题

项目摘要

Abstract Over the last decade, an important paradigm has emerged in which conformationally-altered proteins or protein fragments function as endogenous inhibitors of angiogenesis. The parental proteins that give rise to these polypeptides are often members of the family of coagulation and fibrinolytic proteins, or constituents of the extracellular matrix. Recent studies in our laboratory have focused on the mechanisms by which cleaved high molecular weight kininogen (HKa), a member of the intrinsic coagulation pathway, induces apoptosis of proliferating endothelial cells and inhibits angiogenesis. Though HKa inhibits angiogenesis, recent studies in the BN-Ka rat, in which a point mutation in the kininogen gene results in deficient kininogen secretion, suggest that kininogen deficiency results in decreased angiogenesis and tumor growth. This has been attributed to deficient release of bradykinin (BK) from single chain high molecular weight kininogen (HK), leading to diminished activation of stromal BK B2 receptors and subsequent decreases in stromal VEGF secretion. To further investigate this issue, we have deleted one of the two murine kininogen genes (mKng1). Screening of mKng1-/- mice by immunoblotting using several different kininogen antibodies as well as a sensitive BK radioimmunoassay, demonstrates that these animals are completely deficient in kininogen. In direct contradistinction to the BN-Ka rat, preliminary studies in mKng1-/- mice demonstrate that both angiogenesis and tumor growth are increased. We hypothesize that increased angiogenesis in mKng1-/- mice results from deficient generation of antiangiogenic HKa at sites of active angiogenesis. Since, compared to the rat, the kinin-kallikrein system of the mouse more closely resembles that of the human, we believe that the mKng1-/- mouse provides an important and relevant model for assessing regulation of angiogenesis by kininogen. In this application, we propose to assess the mechanisms underlying the proangiogenic phenotype of mKng1-/- mice through three specific aims. In Specific Aim 1, we will compare tissue morphology, baseline microvascular density, three-dimensional vascular architecture, and the angiogenic response to pathophysiological stimuli in wild type and mKng1-/- mice. These studies will employ newly-developed, automated vessel counting techniques, as well as novel approaches to analysis of three-dimensional vascular morphology. In Specific Aim 2, we will determine whether enhanced angiogenesis in mKng1-/- mice is reversed by replenishment of HK, and whether cleavage of HK to HKa is necessary for reversion to the wild- type phenotype. These studies will employ lentivirus-produced murine HK, as well as a mutant HK resistant to cleavage by kallikrein. In Specific Aim 3, we will assess several important mechanistic issues of potential relevance to the proangiogenic phenotype of mKng1-/- mice, including the levels of circulating endothelial progenitor cells and their ability to home to neovasculature, the intrinsic "angiogenic potential" of mKng1-/- endothelial cells, the role of the uPAR as an "antiangiogenic" HKa receptor, and the importance of oxidative stress to the anti-endothelial cell effects of HKa in vivo. Our observations in mKng1-/- mice establish HK as one of the few genetically-proven endogenous regulators of angiogenesis, and the proposed studies should provide important insight into the mechanisms underlying its activity.
摘要 在过去的十年中,出现了一种重要的范式,其中构象改变的蛋白质或蛋白质 片段作为血管生成的内源性抑制剂发挥作用。产生这些的亲本蛋白质 多肽通常是凝血和纤维蛋白溶解蛋白家族的成员,或凝血和纤维蛋白溶解蛋白的组分。 细胞外基质我们实验室最近的研究集中在切割高分子的机制上, 分子量激肽原(HKa)是内源性凝血途径的一员,可诱导 增殖内皮细胞并抑制血管生成。虽然HKA抑制血管生成,但最近的研究表明, 在BN-Ka大鼠中,激肽原基因的点突变导致激肽原分泌缺陷,提示 激肽原缺乏导致血管生成和肿瘤生长减少。这被归因于 缓激肽(BK)从单链高分子量激肽原(HK)释放不足,导致 基质BK B2受体活化减弱,随后基质VEGF分泌减少。到 为了进一步研究这个问题,我们删除了两个鼠激肽原基因之一(mKng 1)。筛选 使用几种不同的激肽原抗体以及敏感的BK 放射免疫分析表明这些动物完全缺乏激肽原。直接 与BN-Ka大鼠不同,mKng 1-/-小鼠的初步研究表明, 肿瘤的生长也会增加我们假设mKng 1-/-小鼠血管生成增加导致 在活跃的血管生成部位产生的抗血管生成HKA不足。因为,与 大鼠,小鼠的激肽-激肽释放酶系统更接近于人类,我们相信, mKng 1-/-小鼠提供了一个重要的和相关的模型,用于评估血管生成的调节, 激肽原在本申请中,我们建议评估促血管生成表型的机制 mKng 1-/-小鼠的三个具体目标。在特定目标1中,我们将比较组织形态、基线 微血管密度,三维血管结构,以及血管生成反应, 在野生型和mKng 1-/-小鼠中的病理生理刺激。这些研究将采用新开发的, 自动血管计数技术,以及分析三维血管的新方法, 形态学在特异性目标2中,我们将确定mKng 1-/-小鼠中增强的血管生成是否是 通过补充HK逆转,以及HK裂解为HKa是否是回复到野生状态所必需的- 型表型。这些研究将使用慢病毒产生的小鼠HK,以及对HLA-DR具有抗性的突变HK。 由激肽释放酶裂解。在具体目标3中,我们将评估潜在的几个重要机制问题, 与mKng 1-/-小鼠的促血管生成表型相关,包括循环内皮细胞水平 祖细胞及其归巢至新血管的能力,mKng 1-/-的内在“血管生成潜力”, 内皮细胞,uPAR作为一种“抗血管生成”HKa受体的作用,以及氧化应激的重要性。 应激对HKa体内抗内皮细胞作用的影响。我们在mKng 1-/-小鼠中的观察确定HK为 是为数不多的经遗传学证实的血管生成内源性调节因子之一, 提供了重要的洞察其活动的机制。

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Lipocalin-2 released in response to cerebral ischaemia mediates reperfusion injury in mice.
lipocalin-2响应脑缺血介导小鼠的再灌注损伤。
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Keith R. McCrae其他文献

Role of Interferon-Gamma (IFN-γ) Signaling in Immune Checkpoint Inhibitor-Associated Thrombosis: Tissue Factor Upregulation and Proinflammatory Cytokine Signature
  • DOI:
    10.1182/blood-2024-207751
  • 发表时间:
    2024-11-05
  • 期刊:
  • 影响因子:
  • 作者:
    Young Jun Shim;Keith R. McCrae
  • 通讯作者:
    Keith R. McCrae
Concordance between Acr/EULAR and Sapporo Criteria for Antiphospholipid Syndrome: New Domains Unveil Associations with Procoagulant Platelets
  • DOI:
    10.1182/blood-2024-211423
  • 发表时间:
    2024-11-05
  • 期刊:
  • 影响因子:
  • 作者:
    Maierdan Palihati;Anne K Hubben;Kelsey Pandrangi;Paresh P Kulkarni;Keith R. McCrae
  • 通讯作者:
    Keith R. McCrae
Idiopathic multicentric Castleman disease - TAFRO results in high levels of mTOR activator SVEP1, tissue factor, and endotheliopathy
  • DOI:
    10.1016/j.bvth.2024.100006
  • 发表时间:
    2024-06-01
  • 期刊:
  • 影响因子:
  • 作者:
    Chen Lossos;Jenna Brown;Sara Sheikhbahaei;Anne Hubben;Sharon C. Liu;Keith R. McCrae;Shruti Chaturvedi;Rakhi P. Naik;Ivo M.B. Francischetti
  • 通讯作者:
    Ivo M.B. Francischetti
The Bioluminescent Modified Ham Test Identifies the Classical Pathway As the Major Driver of Complement Activation in Atypical Hemolytic Uremic Syndrome and Primary Antiphospholipid Syndrome
  • DOI:
    10.1182/blood-2023-190615
  • 发表时间:
    2023-11-02
  • 期刊:
  • 影响因子:
  • 作者:
    Michael Cole;Gloria F. Gerber;Xiang-Zuo Pan;Nikhil Ranjan;John Sperati;Shruti Chaturvedi;Keith R. McCrae;Robert A. Brodsky
  • 通讯作者:
    Robert A. Brodsky
Programmed Death Ligand 1 Is Released in Platelet-Derived Extracellular Vesicles
  • DOI:
    10.1182/blood-2022-170261
  • 发表时间:
    2022-11-15
  • 期刊:
  • 影响因子:
  • 作者:
    Anne K. Hubben;Young Jun Shim;Suman Kundu;Scott J. Cameron;Keith R. McCrae
  • 通讯作者:
    Keith R. McCrae

Keith R. McCrae的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Keith R. McCrae', 18)}}的其他基金

1/2 Pomalidomide for Bleeding in Patients with Hereditary Hemorrhagic Telangiectasia (HHT)
1/2 Pomalidomide 用于治疗遗传性出血性毛细血管扩张症 (HHT) 患者的出血
  • 批准号:
    10026357
  • 财政年份:
    2020
  • 资助金额:
    $ 37.34万
  • 项目类别:
1/2 Pomalidomide for Bleeding in Patients with Hereditary Hemorrhagic Telangiectasia (HHT)
1/2 Pomalidomide 用于治疗遗传性出血性毛细血管扩张症 (HHT) 患者的出血
  • 批准号:
    10581634
  • 财政年份:
    2020
  • 资助金额:
    $ 37.34万
  • 项目类别:
1/2 Pomalidomide for Bleeding in Patients with Hereditary Hemorrhagic Telangiectasia (HHT)
1/2 Pomalidomide 用于治疗遗传性出血性毛细血管扩张症 (HHT) 患者的出血
  • 批准号:
    10385804
  • 财政年份:
    2020
  • 资助金额:
    $ 37.34万
  • 项目类别:
Efficacy of Pomalidomide in HHT-related bleeding
泊马度胺治疗 HHT 相关出血的疗效
  • 批准号:
    9103200
  • 财政年份:
    2014
  • 资助金额:
    $ 37.34万
  • 项目类别:
Efficacy of Pomalidomide in HHT-related bleeding
泊马度胺治疗 HHT 相关出血的疗效
  • 批准号:
    8914664
  • 财政年份:
    2014
  • 资助金额:
    $ 37.34万
  • 项目类别:
Efficacy of Pomalidomide in HHT-related bleeding
泊马度胺治疗 HHT 相关出血的疗效
  • 批准号:
    8748760
  • 财政年份:
    2014
  • 资助金额:
    $ 37.34万
  • 项目类别:
Regulation of Angiogenesis by Kininogen
激肽原对血管生成的调节
  • 批准号:
    7590813
  • 财政年份:
    2008
  • 资助金额:
    $ 37.34万
  • 项目类别:
Regulation of Angiogenesis by Kininogen
激肽原对血管生成的调节
  • 批准号:
    7746356
  • 财政年份:
    2008
  • 资助金额:
    $ 37.34万
  • 项目类别:
Regulation of Angiogenesis by Kininogen
激肽原对血管生成的调节
  • 批准号:
    7992367
  • 财政年份:
    2008
  • 资助金额:
    $ 37.34万
  • 项目类别:
Regulation of Angiogenesis by Kininogen
激肽原对血管生成的调节
  • 批准号:
    8033860
  • 财政年份:
    2008
  • 资助金额:
    $ 37.34万
  • 项目类别:

相似海外基金

Development of Novel Lung Cancer Therapy Using Tumor-Specific Angiogenesis Inhibitors and Drug Repositioning
使用肿瘤特异性血管生成抑制剂和药物重新定位开发新型肺癌疗法
  • 批准号:
    21H03019
  • 财政年份:
    2021
  • 资助金额:
    $ 37.34万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Development of biomarkers related to drug resistance of angiogenesis inhibitors
血管生成抑制剂耐药性相关生物标志物的开发
  • 批准号:
    20K08542
  • 财政年份:
    2020
  • 资助金额:
    $ 37.34万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Structural and Functional Studies of Brain Angiogenesis Inhibitors (BAIs/ADGRBs)
脑血管生成抑制剂 (BAIs/ADGRB) 的结构和功能研究
  • 批准号:
    9813883
  • 财政年份:
    2019
  • 资助金额:
    $ 37.34万
  • 项目类别:
Elucidation of proteinuria expression mechanism by angiogenesis inhibitors and research on adverse effect avoidance
血管生成抑制剂蛋白尿表达机制的阐明及不良反应避免的研究
  • 批准号:
    17K08457
  • 财政年份:
    2017
  • 资助金额:
    $ 37.34万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Evaluation of cardiotoxicity and elucidation of cardiotoxic molecular mechanisms in cancer patients receiving angiogenesis inhibitors
接受血管生成抑制剂的癌症患者的心脏毒性评估和心脏毒性分子机制的阐明
  • 批准号:
    26461102
  • 财政年份:
    2014
  • 资助金额:
    $ 37.34万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Minimally invasive response evaluation in vivo for the dual therapy of the angiogenesis inhibitors
血管生成抑制剂双重治疗的体内微创疗效评价
  • 批准号:
    23591763
  • 财政年份:
    2011
  • 资助金额:
    $ 37.34万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
ANGIOGENESIS INHIBITORS IN THE MULTIMODAL TREATMENT OF PEDIATRIC SOLID TUMORS
血管生成抑制剂在小儿实体瘤多模式治疗中的应用
  • 批准号:
    8309814
  • 财政年份:
    2011
  • 资助金额:
    $ 37.34万
  • 项目类别:
Discovery and Investigation of Novel Angiogenesis Inhibitors Among Existing Drugs
现有药物中新型血管生成抑制剂的发现和研究
  • 批准号:
    7351352
  • 财政年份:
    2008
  • 资助金额:
    $ 37.34万
  • 项目类别:
Discovery and Investigation of Novel Angiogenesis Inhibitors Among Existing Drugs
现有药物中新型血管生成抑制剂的发现和研究
  • 批准号:
    8002099
  • 财政年份:
    2008
  • 资助金额:
    $ 37.34万
  • 项目类别:
Discovery and Investigation of Novel Angiogenesis Inhibitors Among Existing Drugs
现有药物中新型血管生成抑制剂的发现和研究
  • 批准号:
    7537218
  • 财政年份:
    2008
  • 资助金额:
    $ 37.34万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了