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Endothelial cell stability after pericyte loss through the Ang-1/Tie2 pathway

通过 Ang-1/Tie2 途径丢失周细胞后内皮细胞的稳定性

基本信息

批准号：
9192129
负责人：
Samantha Paulsen
金额：
$ 4.36万
依托单位：
RICE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9192129
关键词：
ANGPT1 gene Adult Affect Age Alzheimer&apos s Disease Apoptosis Basement membrane Binding Blindness Blood Vessels Blood capillaries Cardiovascular system Cell Communication Cell Line Cell Survival Cell physiology Cells Coculture Techniques Controlled Environment Diabetic Retinopathy Diffusion Disease Disease Progression Embryonic Development Endothelial Cells Event Eye diseases Fibrin Functional disorder Ganciclovir Gel Heart Herpesvirus 1 Human In Vitro Intercellular Junctions Link Malignant Neoplasms Measures Mesenchymal Modeling Molecular Mus Nutrient Oxygen Pathway interactions Pericytes Permeability Pharmaceutical Preparations Phenotype Receptor Protein-Tyrosine Kinases Recruitment Activity Research Retinal Role Signal Pathway Signal Transduction System Testing Thymidine Kinase Tissue Engineering Tissues Work body system capillary cell type diabetic in vitro Model in vivo in vivo Model induced pluripotent stem cell killings migration monolayer mouse model stem suicide gene therapeutic target vascular abnormality

项目摘要

PROJECT SUMMARY/ABSTRACT Endothelial cells are the primary components of capillaries, which are present in nearly every tissue of the body and are essential for efficient delivery of oxygen and nutrients to metabolically active tissues. Within capillaries, the function of endothelial cells (ECs) is regulated in part by pericytes, specialized perivascular cells that regulate vessel permeability, stability, and remodeling. One of the primary signaling pathways responsible for pericyte- EC interactions is the angiopoietin-1 (Ang-1)/ Tie2 pathway. Pericytes produce Ang-1, which binds to the Tie2 tyrosine kinase receptor expressed by nearby endothelial cells and promotes EC remodeling, inhibits EC apoptosis, decreases EC layer permeability, and promotes the integrity of EC monolayers. Recent research has identified pericyte loss or dysfunction as a key contributor to the progression of many diseases such as cancer, Alzheimer’s disease, and diabetic retinopathy. Though many studies have used in vivo mouse models to elucidate the role of pericyte loss in capillary dysfunction and disease progression, in vivo models often lack the desired experimental control and rely heavily on non-human cells. To overcome these challenges, we propose to analyze the role of pericyte-EC interactions in stabilizing EC function using human cells in a highly controlled in vitro vascular model. Using 3D fibrin gels containing EC-lined channels and pericytes throughout the bulk of the gel, we will assess how pericytes alter EC function on both a macroscopic and single-cell scale. Then, to mimic the pericyte loss that occurs during diabetic retinopathy, we will selectively induce apoptosis in pericytes using the herpes simplex virus-1 thymidine kinase (HsvTK) system. By transducing pericytes with the ‘suicide gene’ HsvTK we can selectively induce apoptosis in pericytes by adding the drug Ganciclovir. We will assess EC function by measuring diffusion across the EC layer, expression of cell-cell junctions, basement membrane formation, and EC survival, sprouting, and migration. Finally, we will assess the ability of exogenous Ang-1 to restore stable EC function following pericyte loss. We hypothesize that pericyte loss will induce increased permeability of the EC layer, decrease expression of cell-cell junctions, and decrease EC survival and proliferation. Additionally, we expect that exogenous Ang-1 will encourage a stable EC phenotype following low levels of pericyte loss. This project will help us understand the role of pericyte loss in the progression of diseases such as cancer, Alzheimer’s disease, and diabetic retinopathy. Using a highly controlled in vitro model we can better elucidate the molecular events contributing to disease progression and test potential therapeutic targets for these diseases in a highly controlled environment using human cells.

项目总结/文摘