Investigating deskmoplakin during vasculogenesis

超出提供的空间。DP是细胞黏附连接的关键成分，称为桥粒；然而，最近的研究表明，DP在与桥粒分离的连接中有一个新的位置，称为复合体粘连连接。这些连接位于毛细血管内皮细胞之间的接触点。很少有研究集中于DP在发育或肿瘤发生过程中的新生毛细血管形成(血管生成)和分支(血管生成)中的作用。直到最近，才有研究开始确定在胚胎发育过程中(即在DP-/-小鼠中)，DP的丢失对毛细血管的影响。因此，这项拟议研究的目标是确定DP在胚胎和肿瘤中毛细血管形成过程中复合体粘连连接中的功能，并将这一知识应用于抑制肿瘤生长。初步证据表明，在体内和体外，桥粒蛋白的丢失都会导致毛细血管泄漏和/或毛细血管不稳定(Gallicano等人，2001年)。肿瘤发生和胚胎发生一样，高度依赖于血管生成和血管生成。没有毛细血管，胚胎就不能发育。同样，如果没有毛细血管，肿瘤也不会发展，如果已经形成，也会经历坏死。根据这一建议中描述的证据，假设在可诱导启动子的严格调控下，毛细血管内皮细胞内DP的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)。为了检验这一假说，本文提出了三个具体目标。使用最近引入的工具和实验方法，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，然后评估它们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对发育和肿瘤生长过程中的血管和血管生成提供新的见解，并可能为抑制肿瘤的发生提供新的方法。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. 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 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. PERFORMANCE SITE ========================================Section End===========================================