Human Genetics and Molecular Mechanisms of Vein of Galen Aneurysmal Malformation

Galen 动脉瘤畸形静脉的人类遗传学和分子机制

基本信息

  • 批准号:
    10673038
  • 负责人:
  • 金额:
    $ 55.3万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-07-15 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY The genetic study of severe human congenital cerebrovascular anomalies can shed insight into mechanisms of normal vascular development and identify targets for therapeutic intervention. Vein of Galen aneurysmal malformations (VOGMs) are the most common and severe of pediatric brain arterio-venous malformations (AVMs). Significant gaps in our understanding of the molecular pathogenesis of VOGMs impede the development of improved diagnostic and therapeutic measures. Locus heterogeneity and the sporadic nature of VOGM cases have constituted fundamental obstacles to VOGM gene discovery. We recently applied whole exome sequencing (WES) to overcome these obstacles and identified de novo and inherited gene mutations that account for ~30% of sporadic VOGM cases (Duran et al., Neuron, 2019). These included a genome-wide significant burden of rare, damaging mutations in EPHB4 (EphB4), a critical regulator of arterio-venous specification also mutated in the familial AVM syndrome, capillary malformation (CM)-AVM type II (CM-AVM2). We also discovered new mutations in other genes that function in the same Ephrin signaling interactome, including RASA1 (also mutated in CM-AVM1). We further demonstrated that EphB4 exists in a physical complex with RASA1, and have now solved the first multi-domain crystal structure of RASA1. Nonetheless, most VOGM cases remain genetically unsolved, and the molecular mechanisms of VOGM-associated mutations are poorly understood. To address these knowledge gaps, we propose a functional genomics approach to discover and mechanistically elucidate VOGM-associated mutations with atomic-level resolution. We hypothesize WES will identify novel VOGM genes and mutations, including mosaic and somatic “second-hit” mutations, which disrupt the regulated activity of an EphB4-RASA1 signaling complex essential for arterio-venous development. Based on our successful experience in identifying structural brain disorder genes over the past several years, Aim 1 will ascertain additional VOGM case-parent trios and perform WES on our growing cohort (already the largest in the world) to discover novel de novo and transmitted germline VOGM gene mutations, mosaic variants, and somatic mutations in lesional tissue. In Aim 2, we will determine the structural and functional impact of VOGM mutations using biochemical, biophysical, structural biology and cell biology techniques, with validation experiments in autopsied VOGM tissue, and in skin biopsies of VOGM patients with associated cutaneous vascular malformations. Successful completion of these Aims will increase our understanding of human cerebrovascular development and VOGM pathophysiology. These advances will improve disease management and genetic counseling, and will stimulate development of targeted therapeutics for VOGMs that may be broadly relevant for other vascular lesions, including AVMs and intracranial aneurysms.
项目摘要 严重人类先天性脑血管异常的遗传研究可以洞悉 正常的血管发育并确定治疗干预的靶标。 Galen动脉瘤的静脉 畸形(VOGM)是小儿大脑动脉畸形的最常见和严重的 (AVMS)。在我们对VOGM分子发病机理的理解中的显着差异阻碍了 发展改进的诊断和治疗措施。基因座异质性和零星性质 VOGM病例构成了VOGM基因发现的基本障碍。我们最近应用了 外显子组测序(WES)克服这些障碍并鉴定出从头开始并遗传基因突变 该占零星VOGM病例的约30%(Duran等,Neuron,2019)。这些包括全基因组 EPHB4(EPHB4)的稀有,破坏性突变的显着燃烧,EPHB4(EPHB4)的关键调节剂 规格也在家庭AVM综合征,毛细血管畸形(CM)-AVM II型(CM-AVM2)中突变。 我们还发现了其他基因中的新突变,这些突变在相同的以ephrin信号相互作用组中起作用, 包括RASA1(也在CM-AVM1中突变)。我们进一步证明了EPHB4存在于物理中 与RASA1复合物,现在已经解决了RASA1的第一个多域晶体结构。尽管如此, 大多数VOGM病例仍然尚未解决,并且与VOGM相关的分子机制 突变知之甚少。为了解决这些知识差距,我们提出了功能基因组学 通过原子级分辨率发现和机械阐明与VOGM相关的突变的方法。 我们假设WES将识别新的VOGM基因和突变,包括镶嵌和躯体 “第二击”突变,破坏了EPHB4-RASA1信号传导复合物的调节活性 对于动脉预期的发展至关重要。基于我们成功识别结构大脑的经验 在过去的几年中,AIM 1将确定额外的VOGM案例三重奏和 在我们不断发展的队列(已经是世界上最大的)中表演WES,以发现新小说和 病变组织中传播的种系VOGM基因突变,镶嵌变体和体细胞突变。目标 2,我们将使用生化,生物物理,确定VOGM突变的结构和功能影响 结构生物学和细胞生物学技术,在尸体voGM组织中进行验证实验,并在 与皮肤血管畸形的VOGM患者的皮肤活检。成功完成 这些目的将增加我们对人类脑血管发育和VOGM的理解 病理生理学。这些进步将改善疾病管理和遗传咨询,并将 刺激可能与其他血管广泛相关的VOGM的有针对性疗法的发展 病变,包括AVM和颅内动脉瘤。

项目成果

期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Rho family GTPase signaling through type II p21-activated kinases.
  • DOI:
    10.1007/s00018-022-04618-2
  • 发表时间:
    2022-11-19
  • 期刊:
  • 影响因子:
    8
  • 作者:
    Chetty, Ashwin K.;Ha, Byung Hak;Boggon, Titus J.
  • 通讯作者:
    Boggon, Titus J.
Structure Determination of SH2-Phosphopeptide Complexes by X-Ray Crystallography: The Example of p120RasGAP.
通过 X 射线晶体学测定 SH2-磷酸肽复合物的结构:以 p120RasGAP 为例。
Cation flux through SUR1-TRPM4 and NCX1 in astrocyte endfeet induces water influx through AQP4 and brain swelling after ischemic stroke.
  • DOI:
    10.1126/scisignal.add6364
  • 发表时间:
    2023-06-06
  • 期刊:
  • 影响因子:
    7.3
  • 作者:
  • 通讯作者:
Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations.
  • DOI:
    10.1038/s41467-023-43062-z
  • 发表时间:
    2023-11-17
  • 期刊:
  • 影响因子:
    16.6
  • 作者:
    Zhao, Shujuan;Mekbib, Kedous Y.;van der Ent, Martijn A.;Allington, Garrett;Prendergast, Andrew;Chau, Jocelyn E.;Smith, Hannah;Shohfi, John;Ocken, Jack;Duran, Daniel;Furey, Charuta G.;Hao, Le Thi;Duy, Phan Q.;Reeves, Benjamin C.;Zhang, Junhui;Nelson-Williams, Carol;Chen, Di;Li, Boyang;Nottoli, Timothy;Bai, Suxia;Rolle, Myron;Zeng, Xue;Dong, Weilai;Fu, Po-Ying;Wang, Yung-Chun;Mane, Shrikant;Piwowarczyk, Paulina;Fehnel, Katie Pricola;See, Alfred Pokmeng;Iskandar, Bermans J.;Aagaard-Kienitz, Beverly;Moyer, Quentin J.;Dennis, Evan;Kiziltug, Emre;Kundishora, Adam J.;DeSpenza Jr, Tyrone;Greenberg, Ana B. W.;Kidanemariam, Seblewengel M.;Hale, Andrew T.;Johnston, James M.;Jackson, Eric M.;Storm, Phillip B.;Lang, Shih-Shan;Butler, William E.;Carter, Bob S.;Chapman, Paul;Stapleton, Christopher J.;Patel, Aman B.;Rodesch, Georges;Smajda, Stanislas;Berenstein, Alejandro;Barak, Tanyeri;Erson-Omay, E. Zeynep;Zhao, Hongyu;Moreno-De-Luca, Andres;Proctor, Mark R.;Smith, Edward R.;Orbach, Darren B.;Alper, Seth L.;Nicoli, Stefania;Boggon, Titus J.;Lifton, Richard P.;Gunel, Murat;King, Philip D.;Jin, Sheng Chih;Kahle, Kristopher T.
  • 通讯作者:
    Kahle, Kristopher T.
The pseudoGTPase group of pseudoenzymes.
  • DOI:
    10.1111/febs.15554
  • 发表时间:
    2020-10
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Stiegler AL;Boggon TJ
  • 通讯作者:
    Boggon TJ
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Titus Jonathon Boggon其他文献

Titus Jonathon Boggon的其他文献

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{{ truncateString('Titus Jonathon Boggon', 18)}}的其他基金

LIM domain kinases: regulation and substrate recognition
LIM 结构域激酶:调节和底物识别
  • 批准号:
    10798525
  • 财政年份:
    2022
  • 资助金额:
    $ 55.3万
  • 项目类别:
LIM domain kinases: regulation and substrate recognition
LIM 结构域激酶:调节和底物识别
  • 批准号:
    10443356
  • 财政年份:
    2022
  • 资助金额:
    $ 55.3万
  • 项目类别:
P21-activated kinases in cell-cell and cell-matrix adhesion signaling
细胞间和细胞基质粘附信号转导中的 P21 激活激酶
  • 批准号:
    10641867
  • 财政年份:
    2020
  • 资助金额:
    $ 55.3万
  • 项目类别:
P21-activated kinases in cell-cell and cell-matrix adhesion signaling
细胞间和细胞基质粘附信号转导中的 P21 激活激酶
  • 批准号:
    10436342
  • 财政年份:
    2020
  • 资助金额:
    $ 55.3万
  • 项目类别:
P21-activated kinases in cell-cell and cell-matrix adhesion signaling
细胞间和细胞基质粘附信号转导中的 P21 激活激酶
  • 批准号:
    10025961
  • 财政年份:
    2020
  • 资助金额:
    $ 55.3万
  • 项目类别:
P21-activated kinases in cell-cell and cell-matrix adhesion signaling
细胞间和细胞基质粘附信号转导中的 P21 激活激酶
  • 批准号:
    10250504
  • 财政年份:
    2020
  • 资助金额:
    $ 55.3万
  • 项目类别:
Human genetics and molecular mechanisms of Vein of Galen aneurysmal malformation
Galen静脉动脉瘤畸形的人类遗传学和分子机制
  • 批准号:
    10033009
  • 财政年份:
    2020
  • 资助金额:
    $ 55.3万
  • 项目类别:
The function of MEKK3 interaction with CCM2
MEKK3与CCM2相互作用的功能
  • 批准号:
    9033126
  • 财政年份:
    2015
  • 资助金额:
    $ 55.3万
  • 项目类别:
The function of MEKK3 interaction with CCM2
MEKK3与CCM2相互作用的功能
  • 批准号:
    8863345
  • 财政年份:
    2015
  • 资助金额:
    $ 55.3万
  • 项目类别:
Investigating cellular function and biochemical mechanism for STK24-CCM3 complex
研究 STK24-CCM3 复合物的细胞功能和生化机制
  • 批准号:
    9020243
  • 财政年份:
    2014
  • 资助金额:
    $ 55.3万
  • 项目类别:

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ACVRL1基因突变导致肺动脉高压患者临床表型异质性的机制研究
  • 批准号:
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  • 批准年份:
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相似海外基金

Human genetics and molecular mechanisms of Vein of Galen aneurysmal malformation
Galen静脉动脉瘤畸形的人类遗传学和分子机制
  • 批准号:
    10033009
  • 财政年份:
    2020
  • 资助金额:
    $ 55.3万
  • 项目类别:
TGF-beta polymorphisms and breast cancer in families
TGF-β 多态性与家族乳腺癌
  • 批准号:
    8134311
  • 财政年份:
    2005
  • 资助金额:
    $ 55.3万
  • 项目类别:
TGF-beta polymorphisms and breast cancer in families
TGF-β 多态性与家族乳腺癌
  • 批准号:
    8301717
  • 财政年份:
    2005
  • 资助金额:
    $ 55.3万
  • 项目类别:
TGF-beta polymorphisms and breast cancer in families
TGF-β 多态性与家族乳腺癌
  • 批准号:
    8520198
  • 财政年份:
    2005
  • 资助金额:
    $ 55.3万
  • 项目类别:
TGF-beta polymorphisms and breast cancer in families
TGF-β 多态性与家族乳腺癌
  • 批准号:
    7785249
  • 财政年份:
    2005
  • 资助金额:
    $ 55.3万
  • 项目类别:
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