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Competition and morphogenesis in tip cell-mediated branching of tubular networks

尖端细胞介导的管状网络分支的竞争和形态发生

基本信息

批准号：
10449287
负责人：
AMIN S GHABRIAL
金额：
$ 33.58万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10449287
关键词：
3-Dimensional Adherens Junction Affect Animals Apical Basic Science Biological Biological Testing Blood Vessels Caliber Cardiovascular system Cavernous Hemangioma Cell fusion Cells Cerebral Infarction Characteristics Chemotactic Factors Cues Defect Distal Drosophila genus Endothelial Cells Endothelium Follow-Up Studies Gases Generations Genes Genetic Genetic Screening Goals Growth Growth Factor Health Human Kruppel-like transcription factors Lead Legal patent Length Lesion Life Maintenance Mediating Membrane Modeling Molecular Molecular Genetics Morphogenesis Mutation NDRG1 gene Organ Orthologous Gene Pathway interactions Phenotype Phosphotransferases Positioning Attribute Process Property Proteomics Respiratory System Role Septate Shapes Side Signal Pathway Signal Transduction Site Stereotyping System Testing Time Tissues Tube Tubular formation Vascular Diseases Vascular System Vertebrates Vesicle Work Zebrafish angiogenesis apical membrane base blind body system cerebral cavernous malformations cofilin genetic analysis genetic approach genetic manipulation germinal center kinases in vivo imaging loss of function migration moesin mutant notch protein novel recruit repaired respiratory response trafficking vascular bed vasculogenesis

项目摘要

Ghabrial – Project Summary To build a functional vascular system, a network of endothelial tubes must be generated through a combination of vasculogenesis and angiogenesis. During sprouting angiogenesis, endothelial tip cells lead the outgrowth of new branches. Tip cells anastomose with other tip cells or with pre-existing tubes. At the same time, tip cells must also lumenize so that the tubes become patent. Studies in zebrafish indicate tip cells lumenize by a process that an intracellular tube that, in cross section, lacks junctional seams (seamless tube). Even tip cells that later remodel to contribute to multicellular tubes, pass through a seamless tube intermediate stage. Likewise, during primary branching of the Drosophila respiratory system, tracheal tip cells lead the outgrowth of new branches. To form a network, some tracheal tip cells anastomose (fusion cells) while others (terminal cells) branch extensively to produce dozens of blind ended tubes that ramify on target tissues and act as the sites of gas exchange. Like endothelial tip cells, tracheal tip cells form seamless tubes. Cell biological studies have led to the current model of seamless tube formation by inverse membrane blebbing; however, very little is known about the genetic and molecular pathways that are required. We have been exploiting the powerful forward genetic approaches possible in Drosophila to meet our long-term objective of pioneering an understanding of the genetic and molecular framework required to make, shape and maintain seamless tubes. The rationale of our approach is that the fundamental rules and genetic pathways operative in Drosophila are likely to be conserved throughout the animal kingdom. As we build our understanding by identifying novel genes required for seamless tube morphogenesis (AIM 1: Determine the molecular identity and function of the cystic lumens gene.), we also go deeper – using molecular genetic, cellular, and proteomic approaches – to identify additional components and mechanisms of action for genetic pathways we have previously identified, and extending our findings to endothelial seamless tubes (AIM 2: Elucidate the cellular and molecular mechanisms of TBC1D10 and Rab35 action in seamless tube growth). Additionally, one seamless tubulogenesis pathway (the Cerebral Cavernous Malformations 3-Germinal Center Kinase III pathway) we identified, is known to be critical in endothelial cells, as mutations in orthologous human genes lead to familial vascular disease. Using Drosophila genetic and proteomic approaches, we have identified factors required both upstream and downstream in the CCM3-GCKIII pathway, and now propose to more clearly define the biological consequences of perturbing the pathway and to identify the downstream targets of the signaling pathway. Given the conserved role of CCM3 in tubulogenesis, we also seek to extend our results to the vertebrate endothelial system, making use of zebrafish, whose unique properties will allow both genetic manipulation and live imaging in vivo of vascular lesion formation (AIM 3: To characterize the role of the NDR kinase, Tricornered, in regulating seamless tube shape.).

加布里埃尔 – 项目摘要为了构建功能性血管系统，必须通过组合生成内皮管网络血管生成和血管生成。在萌芽血管生成过程中，内皮尖端细胞引导生长新的分支机构。尖端细胞与其他尖端细胞或预先存在的管吻合。与此同时，尖端细胞还必须进行内腔化，使管子成为专利。对斑马鱼的研究表明尖端细胞通过细胞内管的横截面缺乏连接缝（无缝管）的过程。甚至尖端细胞后来改造成多细胞管，经过无缝管中间阶段。同样，在果蝇呼吸系统的初级分支期间，气管尖端细胞导致新的分支机构。为了形成网络，一些气管尖端细胞相互吻合（融合细胞），而另一些细胞（末端细胞）则相互吻合。细胞）广泛分支，产生数十个盲端管，这些管在目标组织上分叉并充当气体交换场所。与内皮尖端细胞一样，气管尖端细胞形成无缝管。细胞生物学研究导致了当前通过反膜起泡形成无缝管的模型；然而，很少有了解所需的遗传和分子途径。我们一直在利用强大的力量在果蝇中可能采用先进的遗传方法，以实现我们开拓果蝇的长期目标了解制造、成型和维护无缝管所需的遗传和分子框架。我们方法的基本原理是果蝇中起作用的基本规则和遗传途径是可能在整个动物界得到保护。当我们通过识别小说来建立我们的理解时无缝管形态发生所需的基因（目标 1：确定无缝管形态发生的分子身份和功能囊腔基因。），我们还更深入——使用分子遗传学、细胞和蛋白质组学方法—— 为了确定遗传途径的其他成分和作用机制，我们之前已经确定，并将我们的发现扩展到内皮无缝管（目标 2：阐明细胞和 TBC1D10 和 Rab35 在无缝管生长中作用的分子机制）。另外，一无缝肾小管发生途径（脑海绵状血管畸形 3-生发中心激酶 III 我们发现，已知在内皮细胞中至关重要，因为直系同源人类基因的突变导致家族性血管疾病。使用果蝇遗传学和蛋白质组学方法，我们已经确定 CCM3-GCKIII 通路上游和下游所需的因素，现在建议更多明确定义干扰途径的生物学后果并确定下游目标信号通路。鉴于 CCM3 在肾小管发生中的保守作用，我们还寻求扩展我们的结果脊椎动物内皮系统利用斑马鱼，其独特的特性将允许遗传血管病变形成的体内操作和实时成像（目标 3：表征 NDR 激酶，Tricornered，用于调节无缝管形状。）。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Regulation of Archease by the mTOR-vATPase axis.

mTOR-vATPase 轴对 Archease 的调节。

DOI：
10.1242/dev.200908
发表时间：
2022
期刊：
Development (Cambridge, England)
影响因子：
0
作者：
Francis,Deanne;Burguete,AlondraS;Ghabrial,AminS
通讯作者：
Ghabrial,AminS

Whacked and Rab35 polarize dynein-motor-complex-dependent seamless tube growth.

Whacked 和 Rab35 极化动力蛋白运动复合体依赖性无缝管生长。

DOI：
10.1038/ncb2454
发表时间：
2012
期刊：
Nature cell biology
影响因子：
21.3
作者：
Schottenfeld-Roames,Jodi;Ghabrial,AminS
通讯作者：
Ghabrial,AminS

Seamless tube shape is constrained by endocytosis-dependent regulation of active Moesin.

DOI：
10.1016/j.cub.2014.06.029
发表时间：
2014-08-04
期刊：
CURRENT BIOLOGY
影响因子：
9.2
作者：
Schottenfeld-Roames, Jodi;Rosa, Jeffrey B.;Ghabrial, Amin S.
通讯作者：
Ghabrial, Amin S.

Dissection of the Role of CCM Genes in Tubulogenesis Using the Drosophila Tracheal System as a Model.

使用果蝇气管系统作为模型剖析 CCM 基因在管发生中的作用。

DOI：
10.1007/978-1-0716-0640-7_14
发表时间：
2020
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
SchweizerBurguete,AlondraB;Ghabrial,AminS
通讯作者：
Ghabrial,AminS

A Hippo-like Signaling Pathway Controls Tracheal Morphogenesis in Drosophila melanogaster.

DOI：
10.1016/j.devcel.2018.09.024
发表时间：
2018-12-03
期刊：
Developmental cell
影响因子：
11.8
作者：
Poon CLC;Liu W;Song Y;Gomez M;Kulaberoglu Y;Zhang X;Xu W;Veraksa A;Hergovich A;Ghabrial A;Harvey KF
通讯作者：
Harvey KF