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Novel regulators, components and function of endothelial diaphragms

内皮隔膜的新型调节器、组件和功能

基本信息

批准号：
10339380
负责人：
RADU VIRGIL STAN
金额：
$ 41万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10339380
关键词：
Address Adult Animal Model Antibodies Antigens B-Lymphocytes Basement membrane Biogenesis Biological Assay Biology Blood Blood Vessels Blood capillaries Caveolae Cell Culture System Cell Culture Techniques Cell Line Cell membrane Cell model Cellular Structures Clinic Clinical Collaborations Data Defect Diabetes Mellitus Diarrhea Discontinuous Capillary Disease Endocrine Glands Endothelial Cells Endothelium Exocrine Glands Extracellular Matrix Extracellular Matrix Proteins FGF5 gene FGFR1 gene Fenestrated Capillary Fibrinogen Gene Expression Genetic Engineering Genetically Engineered Mouse Growth Factor Homeostasis Human Immune System Diseases Immune response In Situ Inflammation Integrin Binding Integrins Investigation KDR gene Kidney Diseases Kidney Failure Kidney Glomerulus Knowledge Laboratories Laminin Lead Leukocytes Life Literature Liver Liver diseases MAP Kinase Gene MAPK3 gene MAPK8 gene Maintenance Malignant Neoplasms Medical Microvascular Permeability Modeling Molecular Morphogenesis Mus Myocardial Infarction Nutrient Organ Organelles Outcome Oxygen Pathogenesis Pathway interactions Perinatal mortality demographics Permeability Phenotype Physiological Play Positioning Attribute Pre-Eclampsia Process Property Protein-Losing Enteropathies Proteins Proto-Oncogene Protein c-kit Reagent Receptor Signaling Regulation Regulatory Pathway Research Respiratory Diaphragm Retina Retinal Diseases Role Signal Pathway Signal Transduction Structure of choroid plexus Subcellular structure Syndrome Testing Therapeutic Tissues Toxic Hepatitis Validation Vascular Endothelial Cell Vascular Endothelial Growth Factors Vascular Endothelium Vascular Permeabilities Vesicle Viral Visceral Work base cancer immunotherapy cancer therapy gain of function human disease innovation insight interest loss of function loss of function mutation lymph nodes novel novel therapeutic intervention p38 Mitogen Activated Protein Kinase receptor reconstitution tool tumor growth vascular bed wasting

项目摘要

Endothelial diaphragms are protein barriers associated with vascular endothelial subcellular structures, such as fenestrae, transendothelial channels (TEC), caveolae and vesiculo-vacuolar organelles implicated in vascular permeability and immune response. Fenestrae are circular transcellular pores in vascular endothelial cells playing critical roles in the maintenance of basal permeability. Recent data in humans and mice demonstrate that fenestrae and their diaphragms play critical roles in the maintenance of normal endothelial barrier function, blood homeostasis and ultimately survival. Our group demonstrated that Plasmalemma Vesicle Associated Protein (PLVAP or PV1) is critical for diaphragm assembly, and that absence of PV1 in mice and humans causes abnormal fenestrae and perinatal lethality due to multiple vascular defects. PV1 is also critical in the immune response, and therapeutic strategies based on PV1 biology are being developed for myocardial infarction, immune diseases and cancer. While there is emerging interest in diaphragms and fenestrae in the clinic, there is a significant knowledge gap in our understanding of the components and regulatory pathways governing fenestrae and diaphragm morphogenesis, addressed in this proposal. Critically for this proposal, PV1 is the only known marker for diaphragms, and we will exploit this property in our investigation of regulation diaphragm morphogenesis. Based on our preliminary data and literature, our central hypothesis is that multiple signaling pathways synergize in vascular bed specific manner for diaphragm and fenestrae formation. Specifically, crosstalk between growth factors and laminin binding integrin receptors are critical for PV1 expression and fenestrae and diaphragm morphogenesis. This hypothesis is based on our key new observations including: 1) differential segmental and spatial control of fenestrae in different vascular beds; 2) Gene expression screens for factors involved in PV1 regulation, identified SCF, FGF-5, VEGF-A and specific laminins signaling via their respective c-KIT, FGFR1, VEGFR2, and ITGB1 receptors as necessary for PV1 expression in ERK1/2 dependent manner; and 3) the combination of laminin with SCF, FGF-5 and VEGF- A results in robust PV1 expression and de novo fenestrae formation We will test our hypothesis using a combination of functionally validated endothelial cell culture systems and genetically engineered animal models using loss of function, gain of function and reconstitution approaches. Our Aims will define the role and downstream signaling pathways of newly identified growth factors and laminins and their integrin receptors regulating PV1 expression and fenestrae morphogenesis. We are uniquely positioned both in terms of key and necessary expertise to complete this work. These investigations will define regulatory factors and pathways controlling the assembly for an intricate and physiologically relevant cellular structure, providing valuable insight that is currently lacking.

内皮隔膜是与血管内皮亚细胞结构相关的蛋白质屏障