Investigating deskmoplakin during vasculogenesis

研究血管生成过程中的 deskmoplakin

• 批准号: 6989775
• 负责人: G IAN GALLICANO
• 金额: $ 26.52万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6989775
• 关键词: angiogenesis; capillary; cell adhesion molecules; embryogenesis; embryonic stem cell; gene mutation; genetically modified animals; intercellular connection; laboratory mouse; mammalian embryology; neoplasm /cancer blood supply; neoplastic growth; protein structure function; transfection /expression vector; vascular endothelium

DESCRIPTION (provided by applicant): DP is a key component of cellular adhesion junctions known as desmosomes; however, recent investigations have demonstrated a novel location for DP in junctions separate from desmosomes termed complexes adherens junctions. These junctions are found at contact sites between endothelial cells that line capillaries. Few studies have focused on the function of DP in de novo capillary formation (vasculogenesis) and branching (angiogenesis) during development or tumorigenesis. Only recently have investigations begun to determine the affect the loss of DP has on capillaries during embryogenesis (i.e., in DP-/- mice). Consequently, the goal of the proposed research is to determine the function of DP in complexus adherens junctions during capillary formation in embryos and tumors, and apply that knowledge to inhibiting tumor growth. Preliminary evidence shows that the loss of desmoplakin both in vivo and in vitro results in leaky capillaries and/or capillary destabilization (Gallicano et al., 2001). Tumorigenesis, like embryogenesis, is highly reliant on both vasculogenesis and angiogenesis. Without capillaries, an embryo fails to develop. Likewise, without capillaries a tumor also fails to develop or undergoes necrosis if already formed. Based on evidence described in this proposal, it is hypothesize that under strict regulation by an inducible promoter either ablation of, or mutation of, DP in endothelial cells lining capillaries will result in tumor inhibition or necrosis (if already formed) due to the disruption of the capillary network. Three Specific Aims are proposed to test this hypothesis. Using recently introduced tools and experimental approaches, it will be possible to identify distinct defects during development and to manipulate activation or repression of DP function within the embryo (as well as in tumors) followed by assessment of their effects on capillary formation and structure. The knowledge gained from this research will provide novel insights into vasculo- and angiogenesis during developmental and tumor growth and possibly provide novel approaches for inhibiting tumorigenesis.

描述（由申请人提供）：DP是细胞粘附连接的关键组成部分，称为脱糖体；然而，最近的研究表明，DP在与称为复合物粘附连接的连接体中的新位置。这些连接在毛细管线的内皮细胞之间的接触位点发现。很少有研究集中在DP在发育或肿瘤发生过程中DP中DP的功能（血管生成）和分支（血管生成）。直到最近，研究才开始确定DP在胚胎发生过程中对毛细血管的影响（即在DP - / - 小鼠中）。因此，拟议的研究的目的是确定DP在胚胎和肿瘤中毛细血管形成过程中复合物粘附连接中的功能，并将这些知识应用于抑制肿瘤生长。初步证据表明，在体内和体外丧失了脱氨木蛋白的丧失会导致毛细血管渗漏和/或毛细血管破坏（Gallicano等，2001）。肿瘤发生，例如胚胎发生，高度依赖于血管生成和血管生成。没有毛细血管，胚胎就无法发展。同样，如果没有毛细血管，则肿瘤也不会发育或发生坏死。基于该提案中描述的证据，假设在诱导型启动子严格调节下，毛细管内皮细胞中DP的消融或突变，将导致肿瘤抑制或坏死（如果已经形成），则由于毛细管网络的中断而导致。提出了三个特定目标来检验这一假设。使用最近引入的工具和实验方法，可以在发育过程中确定不同的缺陷，并操纵或抑制胚胎（以及肿瘤中的DP功能），然后评估其对毛细血管形成和结构的影响。这项研究所获得的知识将为发育和肿瘤生长过程中的血管生成和血管生成提供新的见解，并可能提供抑制肿瘤发生的新方法。

项目成果

Novel 5'TOPmRNAs regulated by ribosomal S6 kinase are important for cardiomyocyte development: S6 kinase suppression limits cardiac differentiation and promotes pluripotent cells toward a neural lineage.

受核糖体 S6 激酶调节的新型 5TOPmRNA 对于心肌细胞发育非常重要：S6 激酶抑制限制心脏分化并促进多能细胞向神经谱系发展。

• DOI: 10.1089/scd.2011.0582
• 发表时间: 2012
• 期刊: Stem cells and development
• 影响因子: 4
• 作者: Li,LeeAnn;Larabee,ShannonM;Chen,Shenglin;Basiri,Ladan;Yamaguchi,Seiji;Zakaria,Asif;Gallicano,GIan
• 通讯作者: Gallicano,GIan