Endoglin Regulates Endothelial Survival and Capillary Tube Stability

内皮糖蛋白调节内皮细胞存活和毛细管稳定性

基本信息

  • 批准号:
    8111481
  • 负责人:
  • 金额:
    $ 8.94万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-05-20 至 2011-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Specific Aims Transforming growth factor (TGF-2) super family signaling in endothelial cells regulates essential components of angiogenesis and vascular morphogenesis, including proliferation and capillary tube formation. TGF-2 super family ligands exert their regulatory effects through the endothelial cell specific TGF-2 receptor complex, ALK1 (type I receptor) and endoglin (co-receptor), along with the ubiquitous type I TGF-2 receptor, ALK5, to activate the canonical Smad 1/5/8 and Smad 2/3 pathways, respectively. TGF-2 ligands also signal through non-Smad pathways such as MAPKs and PI3K/Akt, although the underlying mechanisms remain obscure. A critical role for endoglin and ALK1 in TGF-2 signaling in endothelial cells is supported by their mutation resulting in the human vascular disease, hereditary hemorrhagic telangiectasia (HHT1 and 2), embryonic lethal phenotype due to defects in angiogenesis when either endoglin or ALK1 is targeted for deletion in mice, and by the elevated expression of endoglin during inflammation and tumor-induced angiogenesis. While important biological roles for endoglin have been established, the molecular basis for endoglin function in vascular biology remains poorly characterized. Here in vitro angiogenesis assays were employed to investigate precisely when and how endoglin regulates endothelial capillary sprouting and tube formation. Comparison of endoglin-null and wild type endothelial cells revealed that endoglin differentially regulates the stability of capillary sprouts and tubes in response to its physiologically relevant high-affinity ligands, TGF-2 and BMP-9. Specifically, TGF-2 resulted in regression of the capillary sprouts and tube structures, primarily through suppression of endoglin-dependent Akt signaling. Conversely, endoglin enhanced Akt signaling in response to BMP-9 to promote capillary stability. These outcomes are attributed to the association between endoglin and the scaffolding/trafficking protein, GIPC, since disrupting their interaction abrogated such endoglin-dependent effects. Given that I recently reported the enhancement of Smad 1/5/8 signaling through GIPC and endoglin, there exists a potential crosstalk between Akt and endoglin-dependent Smad 1/5/8 signaling, which I propose to investigate. Lastly, I discovered a novel interaction between endogenous endoglin and Akt, a finding that will likely yield new facets of endoglin biology. Based upon these preliminary data, I propose the following hypothesis: Endoglin associates with GIPC to promote angiogenesis by stabilizing endothelial capillaries via BMP-9-dependent Akt activation while destabilizing capillaries via TGF-2-dependent suppression of Akt signaling and cell survival mechanisms. This hypothesis will be addressed by the objectives outlined in two specific aims. PUBLIC HEALTH RELEVANCE: A distinctly innovative aspect of my application is in defining a new signaling role for endoglin in altering endothelial cell behavior. The current paradigm describes endoglin as an auxiliary TGF-2 co-receptor that regulates the balance of two opposing signaling pathways, Smad1/5/8 and Smad2/3, which invoke pro- or antiangiogenic responses, respectively [12-22]. However, several lines of evidence challenge this overly simplistic role for endoglin. First, an embryonic lethal phenotype is observed in mice bearing homozygous deletions [1,2]. Second, the significance of endoglin signaling to the Smad pathways during angiogenesis is not fully understood, since these canonical signal transducers can be activated without endoglin expression [25]. My preliminary findings indicate that endoglin engages other important signaling and cellular functions such as regulating Akt activation and downstream cell survival mechanisms. I have so far characterized the ability for endoglin to differentially regulate Akt activation in response to its direct ligands, TGF-2 and BMP-9. A very intriguing aspect my research proposal tries to address, therefore, is how endoglin recognizes two structurally related ligands to elicit such divergent effects on Akt activation. Another innovative aspect of my research proposal involves the plan to use in vitro model systems that incorporate many, if not all, of the separate components of the angiogenic process, such as endothelial cell proliferation, degradation of basement membrane, migration, alignment, and capillary tube formation. Several groups have employed cell proliferation and migration assays to dissect the mechanisms by which endoglin regulates angiogenesis. However, appropriate in vitro systems that comprise most of the sequential stages of angiogenesis would be favorable to monitor the effects of endoglin during angiogenic progression. Manipulating various conditions such as ligand treatment or effects of altering protein levels, would all be possible. I have begun employing such methods to study endoglin function. My preliminary findings based on capillary tube formation assay suggest that endoglin plays an important role in regulating the stability of sprouted capillary tubes, and that this dynamic process is largely governed by Akt signaling and cell survival mechanisms. How endoglin might contribute to the stability of these maturing vessels during angiogenesis is an entirely unexplored area of research, and the basis of my research plan. By employing several new in vitro angiogenesis assays including micro- carrier and co-culturing methods, the proposed work will yield significant insight into when and how endoglin exerts its effects during angiogenesis.
描述(由申请方提供):特定目的内皮细胞中的转化生长因子(TGF-2)超家族信号传导调节血管生成和血管形态发生的基本组分,包括增殖和毛细血管形成。TGF-2超家族配体通过内皮细胞特异性TGF-2受体复合物ALK 1(I型受体)和内皮糖蛋白(共受体)发挥其调节作用,沿着普遍存在的I型TGF-2受体ALK 5,以分别激活经典的Smad 1/5/8和Smad 2/3途径。TGF-2配体也通过非Smad途径如MAPK和PI 3 K/Akt信号传导,尽管潜在的机制仍然不清楚。内皮糖蛋白和ALK 1在内皮细胞中的TGF-2信号传导中的关键作用由其突变支持,所述突变导致人血管疾病、遗传性出血性毛细血管扩张症(HHT 1和2)、当内皮糖蛋白或ALK 1在小鼠中靶向缺失时由于血管生成缺陷引起的胚胎致死表型,以及由炎症和肿瘤诱导的血管生成期间内皮糖蛋白的表达升高支持。虽然内皮糖蛋白的重要生物学作用已经确立,但内皮糖蛋白在血管生物学中功能的分子基础仍然缺乏表征。在这里,在体外血管生成试验,以调查究竟何时以及如何endoglin调节内皮毛细血管发芽和管形成。内皮素无效和野生型内皮细胞的比较表明,内皮素差异调节毛细血管芽和管的稳定性,以响应其生理相关的高亲和力配体,TGF-2和BMP-9。具体而言,TGF-2导致毛细血管芽和管结构的退化,主要是通过抑制内皮素依赖性Akt信号传导。相反,endoglin增强Akt信号传导以响应BMP-9,从而促进毛细血管稳定性。这些结果归因于内皮糖蛋白和支架/运输蛋白GIPC之间的关联,因为破坏它们的相互作用消除了这种内皮糖蛋白依赖性作用。鉴于我最近报道了Smad 1/5/8信号通过GIPC和endoglin的增强,Akt和endoglin依赖的Smad 1/5/8信号之间存在潜在的串扰,我建议调查。最后,我发现了内源性endoglin和Akt之间的一种新的相互作用,这一发现可能会产生endoglin生物学的新方面。基于这些初步数据,我提出了以下假设:Endoglin与GIPC通过BMP-9依赖性Akt激活稳定内皮毛细血管,同时通过TGF-2依赖性抑制Akt信号传导和细胞存活机制使毛细血管不稳定,从而促进血管生成。这一假设将通过两个具体目标中概述的目标来解决。 公共卫生相关性:我的申请的一个明显的创新方面是在定义一个新的信号作用内皮糖蛋白在改变内皮细胞的行为。目前的范例将内皮糖蛋白描述为辅助性TGF-2共受体,其调节两种相反的信号传导途径Smad 1/5/8和Smad 2/3的平衡,这两种信号传导途径分别引起促血管生成或抗血管生成反应[12-22]。然而,一些证据对内皮糖蛋白的这种过于简单化的作用提出了挑战。首先,在携带纯合缺失的小鼠中观察到胚胎致死表型[1,2]。其次,血管生成过程中内皮糖蛋白信号传导对Smad通路的重要性尚未完全了解,因为这些经典信号转导子可以在没有内皮糖蛋白表达的情况下被激活[25]。我的初步研究结果表明,endoglin参与其他重要的信号和细胞功能,如调节Akt激活和下游细胞存活机制。到目前为止,我已经描述了内皮糖蛋白响应其直接配体TGF-2和BMP-9差异调节Akt活化的能力。因此,我的研究计划试图解决的一个非常有趣的方面是,内皮糖蛋白如何识别两种结构相关的配体,从而对Akt激活产生如此不同的影响。我的研究建议的另一个创新方面涉及计划使用体外模型系统,该系统包含许多(如果不是全部的话)血管生成过程的单独组分,如内皮细胞增殖、基底膜降解、迁移、对齐和毛细管形成。几个研究小组已经采用细胞增殖和迁移测定来剖析内皮糖蛋白调节血管生成的机制。然而,适当的体外系统,包括大部分的血管生成的顺序阶段将是有利的,以监测血管生成过程中内皮糖蛋白的影响。操纵各种条件,如配体治疗或改变蛋白质水平的影响,都是可能的。我已经开始采用这种方法来研究内皮糖蛋白的功能。基于毛细管形成实验的初步研究结果表明,内皮糖蛋白在调节出芽毛细管的稳定性中起着重要作用,并且这个动态过程在很大程度上受Akt信号传导和细胞存活机制的控制。内皮素如何在血管生成过程中促进这些成熟血管的稳定性是一个完全未探索的研究领域,也是我研究计划的基础。通过采用几种新的体外血管生成检测方法,包括微载体和共培养方法,所提出的工作将产生显着的洞察内皮糖蛋白何时以及如何发挥其作用,在血管生成。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Endoglin inhibits ERK-induced c-Myc and cyclin D1 expression to impede endothelial cell proliferation.
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Nam Y Lee其他文献

Context-dependent activation of
上下文相关的激活
  • DOI:
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Y. Kim;Piyushi Gupta;Victoria M. Jones;B. Worley;Sara Shimko;D. Shin;LaTaijah C. Crawford;Chi;K. Aird;Thomas Abraham;T. Shepherd;J. Warrick;Nam Y Lee;R. Phaeton;K. Mythreye;N. Hempel;MC R130;Ph.D Mythreye Karthikeyan
  • 通讯作者:
    Ph.D Mythreye Karthikeyan

Nam Y Lee的其他文献

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{{ truncateString('Nam Y Lee', 18)}}的其他基金

TGF-beta signaling in mitochondrial dynamics
线粒体动力学中的 TGF-β 信号传导
  • 批准号:
    10550422
  • 财政年份:
    2023
  • 资助金额:
    $ 8.94万
  • 项目类别:
Tumor-intrinsic and paracrine roles of endoglin in pancreatic cancer
内皮糖蛋白在胰腺癌中的肿瘤内在作用和旁分泌作用
  • 批准号:
    10742322
  • 财政年份:
    2023
  • 资助金额:
    $ 8.94万
  • 项目类别:
Role of spectrin signaling complex in angiogenesis
血影蛋白信号复合物在血管生成中的作用
  • 批准号:
    10301004
  • 财政年份:
    2019
  • 资助金额:
    $ 8.94万
  • 项目类别:
Role of spectrin signaling complex in angiogenesis
血影蛋白信号复合物在血管生成中的作用
  • 批准号:
    10061619
  • 财政年份:
    2019
  • 资助金额:
    $ 8.94万
  • 项目类别:
Mechanism of endoglin-targeted anticancer therapy
内皮糖蛋白靶向抗癌治疗机制
  • 批准号:
    8839215
  • 财政年份:
    2014
  • 资助金额:
    $ 8.94万
  • 项目类别:
Mechanism of endoglin-targeted anticancer therapy
内皮糖蛋白靶向抗癌治疗机制
  • 批准号:
    9245653
  • 财政年份:
    2014
  • 资助金额:
    $ 8.94万
  • 项目类别:
Mechanism of endoglin-targeted anticancer therapy
内皮糖蛋白靶向抗癌治疗机制
  • 批准号:
    9036958
  • 财政年份:
    2014
  • 资助金额:
    $ 8.94万
  • 项目类别:
Endoglin Regulates Endothelial Survival and Capillary Tube Stability
内皮糖蛋白调节内皮细胞存活和毛细管稳定性
  • 批准号:
    8585870
  • 财政年份:
    2010
  • 资助金额:
    $ 8.94万
  • 项目类别:
Endoglin Regulates Endothelial Survival and Capillary Tube Stability
内皮糖蛋白调节内皮细胞存活和毛细管稳定性
  • 批准号:
    8459636
  • 财政年份:
    2010
  • 资助金额:
    $ 8.94万
  • 项目类别:
Endoglin Regulates Endothelial Survival and Capillary Tube Stability
内皮糖蛋白调节内皮细胞存活和毛细管稳定性
  • 批准号:
    8529600
  • 财政年份:
    2010
  • 资助金额:
    $ 8.94万
  • 项目类别:

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