Investigating deskmoplakin during vasculogenesis

研究血管生成过程中的 deskmoplakin

• 批准号: 6574003
• 负责人: G IAN GALLICANO
• 金额: $ 25.69万
• 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 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6574003
• 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 是称为桥粒的细胞粘附连接的关键成分；然而，最近的研究表明 DP 在与桥粒分离的连接处有一个新的位置，称为复合物粘附连接。这些连接位于毛细血管内皮细胞之间的接触部位。很少有研究关注 DP 在发育或肿瘤发生过程中毛细血管从头形成（血管生成）和分支（血管生成）中的功能。直到最近，研究才开始确定胚胎发生过程中 DP 丢失对毛细血管的影响（即 DP-/- 小鼠）。因此，本研究的目标是确定胚胎和肿瘤毛细血管形成过程中 DP 在复合体粘附连接中的功能，并将该知识应用于抑制肿瘤生长。初步证据表明，桥粒斑蛋白在体内和体外的损失都会导致毛细血管渗漏和/或毛细血管不稳定（Gallicano 等，2001）。肿瘤发生与胚胎发生一样，高度依赖于血管发生和血管生成。没有毛细血管，胚胎就无法发育。同样，如果没有毛细血管，肿瘤也无法发育或如果已经形成就会坏死。基于该提案中描述的证据，假设在诱导型启动子的严格调控下，毛细血管内皮细胞中的 DP 消融或突变将由于毛细血管网络的破坏而导致肿瘤抑制或坏死（如果已经形成）。提出了三个具体目标来检验这一假设。使用最近推出的工具和实验方法，将有可能识别发育过程中的明显缺陷，并操纵胚胎（以及肿瘤）内 DP 功能的激活或抑制，然后评估其对毛细血管形成和结构的影响。从这项研究中获得的知识将为发育和肿瘤生长过程中的血管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。