Capillary malformation: From somatic GNAQ mutations to disrupted endothelial biology

毛细血管畸形:从体细胞 GNAQ 突变到内皮生物学破坏

基本信息

  • 批准号:
    10058384
  • 负责人:
  • 金额:
    $ 88.94万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-04-01 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

Project Abstract Our studies are focused on capillary malformation (CM) (previously referred to as “port-wine stain”), the most common type of vascular malformation. CM, excessive, enlarged capillary-like vessels just below the surface of the skin, are sporadic congenital lesions that darken, form nodules, and cause soft-tissue and skeletal overgrowth beneath the stain. Sturge-Weber syndrome (SWS) is a neurocutaneous disorder associated with CMs of the face, leptomeninges, and the choroid of the eye; patients suffer from neurological defects and glaucoma. Importantly, drug treatment for CMs does not exist and there is no cure. The 2013 discovery of a somatic activating mutation in GNAQ (p.R183Q) in non-syndromic cutaneous CMs and SWS CMs set the stage for molecular studies of this understudied vascular malformation. GNAQ encodes Gαq, the α-subunit of the heterotrimeric Gq protein that activates phospholipase Cβ. We showed that the GNAQ R183Q allele is enriched in the endothelial cell (EC) sorted from cutaneous CM and SWS brain specimens. We have worked on creating cellular and mouse models to elucidate how the GNAQ mutation affects EC function, how these alterations lead to CM, and how we can prevent the formation or growth of CM. We show that human ECs with the R183Q mutation do not respond properly to laminar shear stress, fail to form an endothelial barrier, and form enlarged CM-like vessels when implanted into mice. We implicate protein kinase C (PKC) and angiopoietin-2 (ANGPT2) as potential targets to reverse the GNAQ R183Q-driven CM. We are making strong progress towards an inducible, endothelial-specific knock-in of Gnaq R183Q in mice in which we have found CM-like lesions upon tamoxifen-induced expression of the knocked-in mutant allele. In this proposal we will identify the breadth of cell types that carry the somatic GNAQ R183Q allele and how the mutation alters the transcriptional profile versus non-mutant cells of the same phenotype (Aim 1). We will develop novel animal models in mice and zebrafish to elucidate the cellular steps leading to CM and will use them as platforms for testing candidate drugs (Aim 2). We will deeply interrogate the role of (ANGPT2) as a downstream functional mediator of constitutively active, mutant Gαq (Aim 3). These studies will deepen our understanding of how Gαq activity participates in capillary morphogenesis, result in the first animal models for CM/SWS, and provide a platform to test drugs that can prevent or regress CM. Discoveries about the pathophysiology of CM will also help us understand the mechanisms that underlie additional vascular lesions and improve our ability to identify new pathways for preventing vascular overgrowth (e.g., cancer) and promoting vascular growth during tissue repair or engineering.
项目摘要 我们的研究重点是毛细血管畸形 (CM)(以前称为“鲜红斑痣”),这是最常见的毛细血管畸形(CM)。 常见类型的血管畸形。 CM,表面下方过多、增大的毛细血管样血管 皮肤的散发性先天性病变,会变黑,形成结节,并导致软组织和骨骼损伤 污渍下方过度生长。斯特奇-韦伯综合征 (SWS) 是一种与以下疾病相关的神经皮肤疾病 面部、软脑膜和眼睛脉络膜的 CM;患有神经系统缺陷的患者 青光眼。重要的是,目前还不存在针对 CM 的药物治疗,也无法治愈。 2013 年在非综合征性皮肤 CM 中发现 GNAQ (p.R183Q) 体细胞激活突变 SWS CM 为这种尚未充分研究的血管畸形的分子研究奠定了基础。 GNAQ 编码 Gαq,异源三聚体 Gq 蛋白的 α 亚基,可激活磷脂酶 Cβ。我们证明了 GNAQ R183Q 等位基因在从皮肤 CM 和 SWS 脑中分选的内皮细胞 (EC) 中富集 标本。我们致力于创建细胞和小鼠模型来阐明 GNAQ 突变是如何发生的 影响 EC 功能,这些改变如何导致 CM,以及我们如何预防 CM 的形成或生长。 我们表明,具有 R183Q 突变的人类 EC 不能正确响应层流剪切应力,无法 形成内皮屏障,并在植入小鼠体内时形成扩大的 CM 样血管。我们牵涉到蛋白质 激酶 C (PKC) 和血管生成素-2 (ANGPT2) 作为逆转 GNAQ R183Q 驱动的 CM 的潜在靶标。 我们正在小鼠体内诱导性内皮特异性敲入 Gnaq R183Q 方面取得了重大进展 我们发现他莫昔芬诱导敲入突变等位基因表达后出现CM样病变。 在本提案中,我们将确定携带体细胞 GNAQ R183Q 等位基因的细胞类型的广度以及如何 与相同表型的非突变细胞相比,突变改变了转录谱(目标 1)。我们将 在小鼠和斑马鱼中开发新型动物模型,以阐明导致 CM 的细胞步骤,并将使用 它们作为测试候选药物的平台(目标 2)。我们将深入探讨(ANGPT2)作为 组成型活性突变体 Gαq 的下游功能介导物(目标 3)。这些研究将加深我们 了解 Gαq 活性如何参与毛细血管形态发生,产生了第一个动物模型 CM/SWS,并提供一个平台来测试可以预防或消退 CM 的药物。关于的发现 CM 的病理生理学还将帮助我们了解其他血管病变的机制 并提高我们发现预防血管过度生长(例如癌症)的新途径的能力,以及 在组织修复或工程过程中促进血管生长。

项目成果

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Joyce E. Bischoff其他文献

Joyce E. Bischoff的其他文献

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{{ truncateString('Joyce E. Bischoff', 18)}}的其他基金

Pediatric Surgeon-Scientist Training Program in Vascular Diseases
小儿外科医生-科学家血管疾病培训计划
  • 批准号:
    10331916
  • 财政年份:
    2022
  • 资助金额:
    $ 88.94万
  • 项目类别:
Pediatric Surgeon-Scientist Training Program in Vascular Diseases
小儿外科医生-科学家血管疾病培训计划
  • 批准号:
    10619547
  • 财政年份:
    2022
  • 资助金额:
    $ 88.94万
  • 项目类别:
Capillary malformation: From somatic GNAQ mutations to disrupted endothelial biology
毛细血管畸形:从体细胞 GNAQ 突变到内皮生物学破坏
  • 批准号:
    10206231
  • 财政年份:
    2016
  • 资助金额:
    $ 88.94万
  • 项目类别:
Capillary malformation: From somatic GNAQ mutations to disrupted endothelial biology
毛细血管畸形:从体细胞 GNAQ 突变到内皮生物学破坏
  • 批准号:
    10630310
  • 财政年份:
    2016
  • 资助金额:
    $ 88.94万
  • 项目类别:
Capillary malformation: From somatic GNAQ mutations to disrupted endothelial biology
毛细血管畸形:从体细胞 GNAQ 突变到内皮生物学破坏
  • 批准号:
    10414083
  • 财政年份:
    2016
  • 资助金额:
    $ 88.94万
  • 项目类别:
Capillary malformation: From somatic GNAQ mutations and disrupted endothelial biology
毛细血管畸形:来自体细胞 GNAQ 突变和内皮生物学破坏
  • 批准号:
    9244833
  • 财政年份:
    2016
  • 资助金额:
    $ 88.94万
  • 项目类别:
Blood vessel assembly from multipotent hemangioma-derived stem cells
来自多能血管瘤干细胞的血管组装
  • 批准号:
    8248244
  • 财政年份:
    2009
  • 资助金额:
    $ 88.94万
  • 项目类别:
Blood vessel assembly from multipotent hemangioma-derived stem cells
来自多能血管瘤干细胞的血管组装
  • 批准号:
    10609870
  • 财政年份:
    2009
  • 资助金额:
    $ 88.94万
  • 项目类别:
Blood vessel assembly from multipotent hemangioma-derived stem cells
来自多能血管瘤干细胞的血管组装
  • 批准号:
    9973341
  • 财政年份:
    2009
  • 资助金额:
    $ 88.94万
  • 项目类别:
Blood vessel assembly from multipotent hemangioma-derived stem cells
来自多能血管瘤干细胞的血管组装
  • 批准号:
    7789467
  • 财政年份:
    2009
  • 资助金额:
    $ 88.94万
  • 项目类别:

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