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Mechanisms for matrix-dependent BBB dysfunction

基质依赖性血脑屏障功能障碍的机制

基本信息

批准号：
10397156
负责人：
Richard Scott Beard
金额：
$ 33.02万
依托单位：
BOISE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10397156
关键词：
AKT2 gene Acute Adhesions Animal Model Basement membrane Blood Blood - brain barrier anatomy Blood Vessels Cell Adhesion Cell Communication Cells Central Nervous System Diseases Collagen Type IV Cues Data Dementia Demyelinating Diseases Development Disease Disease Progression Down-Regulation Encephalopathies Endothelial Cells Endothelium Experimental Autoimmune Encephalomyelitis Experimental Models Extracellular Matrix FOXO1A gene Functional disorder Future Gene Transfer Genetic Transcription Goals Hemorrhage Histopathology Homeostasis Impairment In Vitro Individual Inflammation Inflammation Mediators Inflammatory Injury Integrins Interleukin-1 beta Intervention Knock-in Mouse Knockout Mice Knowledge Laboratories Lesion Leucine Liquid substance Maintenance Mediating Metastatic malignant neoplasm to brain Modeling Molecular Multiple Sclerosis Nerve Degeneration Neuraxis Neuronal Dysfunction Pathogenicity Pathologic Pathway interactions Persons Pharmacology Phase Physiological Protein Isoforms Proteins Proteoglycan Proto-Oncogene Proteins c-akt Regulation Reporting Repression Research Role Signal Pathway Signal Transduction Stroke Surface Techniques Testing Tetanus Helper Peptide Therapeutic Tight Junctions Tissues Transgenic Mice Translating Traumatic Brain Injury United States Up-Regulation Ursidae Family Work autocrine biglycan blood-brain barrier function brain cell cost decorin experimental study expression vector in vivo innovation insight integrin-linked kinase mouse model multiple sclerosis patient neuroinflammation new therapeutic target novel overexpression preservation prevent screening seal solute tool

项目摘要

PROJECT SUMMARY Over the past decade, the importance of the extracellular matrix (ECM) composition surrounding the endothelial cells (ECs) of the blood-brain barrier (BBB) has been increasingly recognized not only in barrier development and maintenance, but also in dysfunction. The tight junction protein claudin-5 (CLDN5) is critical for sealing paracellular pores between ECs to prevent the passage of fluids, solutes, and cells, thereby forming the de facto BBB. Major gaps in knowledge include what ECM alterations occur during inflammatory injuries and how they contribute to barrier disruption, plus how ECM-EC interactions regulate CLDN5. Our long-term goal is to elucidate the endothelial-specific signaling pathways responsible for BBB dysfunction during inflammation. The overall objective of this proposal is to define the role of ECM-mediated dysregulation of CLDN5-dependent BBB function during inflammation. Emphasis is placed on a novel role for the isoform-specific function of AKT2 in maintaining maximal CLDN5 expression during homeostasis, plus a proinflammatory role of two small leucine- rich proteoglycans (SLRPs), decorin and biglycan, in CLDN5 downregulation during neuroinflammation. The central hypothesis is that inflammation triggers a release of endothelial-derived SLRPs which act in an autocrine fashion to interfere with constitutive ECM-dependent regulation of CLDN5, contributing to BBB dysfunction. This hypothesis was derived from preliminary findings generated in the applicant’s laboratory. The rationale for the proposed research is that a better understanding of ECM pathobiology will translate into increased insights of the pathogenic role of BBB dysfunction in a multitude of inflammation-associated diseases in the central nervous system (CNS) which collectively account for the suffering of approximately 9 million people in the United States alone and bear a cost burden of 300 billion dollars annually. Guided by robust preliminary data, this hypothesis will be tested by two specific aims: 1) Determine the role of endothelial-derived SLRPs in BBB dysfunction during inflammation; and 2) Define the role of impaired β1-ILK-AKT2 signaling in ECM-dependent BBB dysfunction. The approach will be multifaceted, combining in vivo physiological analyses in a relevant animal model with comparable ex vivo and in vitro experiments using primary ECs isolated from CNS tissue. Innovative experimental models include transgenic mice with inducible BBB-specific SLRP deficiency or AKT2 overexpression; new molecular tools such as Tet-On constructs for gene transfer of decorin, biglycan, ILK, and AKT2; targeted screening of pharmacologic agents; and state-of-the-art histopathology techniques to detect inflammatory-mediated ECM alterations likely to only be present surrounding a small percentage of CNS microvessels (perivenular inflammatory lesions). The proposed research is significant, as data derived from these studies will not only establish novel concepts in ECM-dependent regulation of the endothelium but will also provide new mechanistic insights into the pathophysiology of BBB dysfunction with the potential to provide a basis for the development of new therapeutictargets.

项目总结