Functional Cooperation of Tissue Factor and Integrins

组织因子和整合素的功能协同

基本信息

批准号：
9249085
负责人：
WOLFRAM RUF
金额：
$ 48.13万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-07-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9249085
关键词：
Address Alternative Splicing Angiogenic Switch Anticoagulants Attenuated Binding Sites Biological Assay Blood Blood Coagulation Factor Cell model Cells Coagulation Process Complex Coupled Cytoplasmic Tail Development Endothelial Cells Extrahepatic Factor VIIa Funding G-substrate GTP-Binding Proteins Generations Genetic Grant Hemostatic Agents Human Immune Impairment Individual Integrin Binding Integrin Signaling Pathway Integrins Knock-in Mouse Length Ligands Ligation Malignant Neoplasms Mammary Neoplasms Modeling Molecular Mus Neoplasm Metastasis Oncogenic PAR-2 Receptor Paracrine Communication Pathway interactions Peptide Hydrolases Pharmacology Physiological Play Protein Isoforms Proteinase-Activated Receptors RNA Splicing Research Role Signal Pathway Signal Transduction Source Specificity System Testing Therapeutic Thrombin Thromboplastin Thrombosis Tumor Angiogenesis Tumor Biology Variant Work Xenograft Model activated protein C receptor angiogenesis base cancer cell cancer stem cell conformer cytokine experimental study human tissue in vivo innovation insight macrophage mouse model mutant neoplastic cell novel pre-clinical public health relevance receptor reconstitution tool tumor tumor growth tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): Tissue factor (TF), the initiator of the extrinsic coagulation pathway, is upregulated in cancer cells and the complex of TF with its ligand coagulation factor VIIa (FVIIa) contributes to cancer- associated thrombosis and activation of the host hemostatic system in metastasis. In addition, cancer cell signaling of the TF-FVIIa complex, in cooperation with the TF cytoplasmic domain, promotes tumor progression in spontaneous murine and human xenograft models by activating proangiogenic cell signaling of the G protein-coupled protease activated receptor (PAR) 2. This pathway can be targeted to attenuate tumor growth in preclinical tumor models. In this renewal application, we address unresolved major questions on the roles of the TF pathway in tumor biology, utilizing newly developed genetic and pharmacological approaches. Aim 1 utilizes an integrin binding-impaired mutant of FVIIa to dissect integrin-dependent and -independent signaling of the TF-FVIIa complex. In addition, characterization of a novel mouse model carrying cleavage-insensitive PAR2 will provide the first definitive distinction of proteolytic and cleavage- independent bystander roles of PAR2 in tumor progression and metastasis. Aim 2 addresses the origin of upstream coagulation proteases that promote tumor growth by activating cancer cell-expressed protease receptors and delineates the respective contributions of FVIIa and FXa to cancer cell PAR2 activation. In Aim 3, the specific functions of TF splice variants in angiogenesis are further elucidated with novel genetic and pharmacological tools. The proposed studies are expected to yield valuable new insights into potential therapeutic approaches to block tumor promoting signaling of the coagulation pathway.

描述（由申请人提供）：外部凝血途径的组织因子（TF）在癌细胞中上调，TF的复合物与其配体凝结因子VIIA（FVIIA）在转移中有助于癌症相关的血栓形成和宿主止血系统的激活。 In addition, cancer cell signaling of the TF-FVIIa complex, in cooperation with the TF cytoplasmic domain, promotes tumor progression in spontaneous murine and human xenograft models by activating proangiogenic cell signaling of the G protein-coupled protease activated receptor (PAR) 2. This pathway can be targeted to attenuate tumor growth in preclinical tumor models.在此续签应用中，我们利用新开发的遗传学和药理方法解决了有关TF途径在肿瘤生物学中的作用的未解决的主要问题。 AIM 1利用FVIIA的整联蛋白结合损伤突变体来剖析整联蛋白依赖性和非依赖性TF-FVIIA复合物的信号传导。此外，携带裂解不敏感PAR2的新型小鼠模型的表征将提供蛋白水解和切割独立的旁观者在肿瘤进展和转移中的独立旁观者的作用。 AIM 2解决了通过激活癌细胞表达的蛋白酶受体促进肿瘤生长的上游凝血蛋白酶的起源，并描绘了FVIIA和FXA对癌细胞PAR2激活的各自贡献。在AIM 3中，TF剪接变体在血管生成中的特定功能进一步用新型的遗传和药理工具阐明。预计拟议的研究将对潜在的治疗方法产生有价值的新见解，以阻止肿瘤促进凝血途径的信号传导。

项目成果

期刊论文数量（31）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Tissue factor and cell signalling in cancer progression and thrombosis.

DOI：
10.1111/j.1538-7836.2011.04318.x
发表时间：
2011-07
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
0
作者：
Ruf W;Disse J;Carneiro-Lobo TC;Yokota N;Schaffner F
通讯作者：
Schaffner F

Engineering of a membrane-triggered activity switch in coagulation factor VIIa.

凝血因子 VIIa 膜触发活性开关的工程设计。

DOI：
10.1073/pnas.1618713114
发表时间：
2017
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Nielsen,AndersL;Sorensen,AndersB;Holmberg,HeidiL;Gandhi,PrafullS;Karlsson,Johan;Buchardt,Jens;Lamberth,Kasper;Kjelgaard-Hansen,Mads;Ley,CarstenDan;Sørensen,BritB;Ruf,Wolfram;Olsen,OleH;Østergaard,Henrik
通讯作者：
Østergaard,Henrik

Role of the protein C receptor in cancer progression.