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

• 批准号: 7670259
• 负责人: Erica Marlis Werner
• 金额: $ 12.77万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-27 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7670259
• 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; Modeling; Mutagenesis; Neoplasms; Normal tissue morphology; Pathway interactions; Pattern; Permeability; Phenotype; Property; Proteins; Publishing; Recombinants; Research Personnel; Role; Signal Transduction Pathway; Site-Directed Mutagenesis; Structure; Testing; Therapeutic Intervention; 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; therapeutic development; therapy development; tumor; tumor endothelial marker 8; tumor progression; vasculogenesis

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）：肿瘤内皮是提供抗血管生成和抗血管靶向治疗癌症的主要关注点。然而，由于缺乏对肿瘤环境中内皮细胞功能的了解，这些治疗策略的发展受到了阻碍。肿瘤内皮标志物8 （TEM8）是肿瘤相关血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已被提出作为抗血管治疗的靶向候选。有趣的是，这种分子也介导炭疽毒素进入细胞。