Tumor Endothelium Marker 8 mediated adhesion in tumor associated vasculature

肿瘤内皮标记物 8 介导的肿瘤相关脉管系统粘附

基本信息

批准号：
7386177
负责人：
Erica Marlis Werner
金额：
$ 12.35万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-27 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7386177
关键词：
Actins Adenoviruses Adhesions Adhesives Anthrax disease Antigens Basement membrane Binding Biological Assay Biological Models Blood Vessels Cell Adhesion Cell Adhesion Molecules Cell Surface Proteins Cell Surface Receptors Cell physiology Cell surface Cells Chickens Chimeric Proteins Collagen Collagen Receptors Cytoskeleton Cytotoxic agent Development Drug usage Endothelial Cells Endothelium Environment Extracellular Domain Extracellular Matrix Future Growth Factor Human Image Injection of therapeutic agent Integral Membrane Protein Intravenous Knowledge Ligand Binding Ligands Maintenance Mediating Membrane Proteins Modeling Mutagenesis Neoplasms Normal tissue morphology Pathway interactions Pattern Permeability Phenotype Property Proteins Publishing Purpose Rate Recombinants Research Personnel Role Signal Transduction Pathway Site-Directed Mutagenesis Structure Testing Therapeutic Therapeutic Intervention Thinking Toxin Tumor Tissue Tumor-Associated Vasculature Tumor-Derived Vascular System Vascularization angiogenesis anthrax toxin antigen binding cancer therapy chorioallantoic membrane crosslink defined contribution extracellular genetic manipulation improved insight interest loss of function mutant novel novel strategies programs receptor research study response therapy development tumor tumor endothelial marker 8 tumor progression vasculogenesis

项目摘要

DESCRIPTION (provided by applicant): The tumor endothelium is a focus of major interest to deliver anti-angiogenic and anti-vascular targeted therapies for cancer treatment. However, the development of these therapeutic strategies has been hampered by the considerable lack of understanding of endothelial cell function in the tumor environment. Tumor endothelium marker 8 (TEM8) is a cell surface receptor selectively induced in tumor-associated vasculature. Because of this restricted expression pattern, TEM8 has been proposed as a targeting candidate for anti-vascular therapies. Interestingly, this molecule also mediates anthrax toxin delivery into cells. Central to this proposal is our finding that TEM8 holds signature features of an adhesion molecule. The purpose of this study is to evaluate the adhesive function of TEM8 and its role in tumor associated vasculature. The proposed specific aims are focused on the features that define TEM8 as an adhesion molecule: 1) to determine whether collagen I is an adhesive ligand for this receptor by performing cell binding and spreading assays. 2) To identify the cytosolic domain determinants necessary to mediate cell spreading and linkage to the actin cytoskeleton by constructing deletion mutants and isolating interacting proteins using the cytosolic domain in pull-down assays. 3) We will explore the role of TEM8 in normal or tumoral vasculature using the chicken chorioallantoic membrane as a model vascular system accessible to genetic manipulation through intravenous delivery of recombinant adenoviruses. In addition, TEM8 expression effects on normal development associated vasculogenesis, growth factor induced angiogenesis and vascularization of tumor grafts will be examined in this model. Given that the development of therapies to target the tumor-associated blood vessels constitutes a promising and novel approach to improve cancer treatment, gaining further understanding of how candidate target molecules, such as TEM8, function in the vasculature, will provide significant and timely insights to optimize these therapeutic interventions.

描述（由申请人提供）：肿瘤内皮是提供用于癌症治疗的抗血管生成和抗血管靶向疗法的主要关注点。然而，由于对肿瘤环境中内皮细胞功能的严重缺乏了解，这些治疗策略的发展受到阻碍。肿瘤内皮标志物 8 (TEM8) 是一种在肿瘤相关脉管系统中选择性诱导的细胞表面受体。由于这种受限的表达模式，TEM8 已被提议作为抗血管治疗的靶向候选药物。有趣的是，这种分子还介导炭疽毒素进入细胞。该提案的核心是我们发现 TEM8 具有粘附分子的标志性特征。本研究的目的是评估 TEM8 的粘附功能及其在肿瘤相关脉管系统中的作用。所提出的具体目标集中在将 TEM8 定义为粘附分子的特征上：1) 通过进行细胞结合和扩散测定来确定胶原蛋白 I 是否是该受体的粘附配体。 2) 通过构建缺失突变体并在下拉分析中使用胞质结构域分离相互作用蛋白，鉴定介导细胞扩散和与肌动蛋白细胞骨架连接所必需的胞质结构域决定因素。 3）我们将使用鸡绒毛尿囊膜作为模型血管系统，通过静脉内递送重组腺病毒进行基因操作，探讨TEM8在正常或肿瘤脉管系统中的作用。此外，将在该模型中检查TEM8表达对正常发育相关的血管生成、生长因子诱导的血管生成和肿瘤移植物的血管化的影响。鉴于针对肿瘤相关血管的疗法的开发构成了改善癌症治疗的一种有前途且新颖的方法，进一步了解候选靶分子（例如 TEM8）如何在脉管系统中发挥作用，将为以下领域提供重要且及时的见解：优化这些治疗干预措施。