Macrophage, blood-brain barrier, and modulation of neurodegeneration

巨噬细胞、血脑屏障和神经变性的调节

基本信息

批准号：
7983551
负责人：
Yuri Persidsky
金额：
$ 25.36万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-05-15 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7983551
关键词：
AIDS Dementia Complex Acute Address Adhesions Affect Animal Model Anti-Inflammatory Agents Anti-Retroviral Agents Anti-inflammatory Area Arts Astrocytes Attenuated Biological Biological Assay Blood Blood - brain barrier anatomy Blood Substitutes Bone Marrow Brain Brain Injuries Brain region CCL2 gene CCR1 gene CCR5 gene CD44 gene CD8-Positive T-Lymphocytes CXCL10 gene CXCR3 gene CXCR4 gene Cell Adhesion Molecules Cell Communication Cell physiology Cells Chemotactic Factors Chronic Coculture Techniques Collaborations Complex Constitution Cytoskeleton Data Development Developmental Therapeutics Program Down-Regulation Drug Delivery Systems Drug Packaging Electrical Resistance Encephalitis Endothelial Cells Evaluation Figs - dietary Foundations Functional disorder Grant HIV-1 Home environment Human Image Image Analysis Imaging Techniques Immigration Immune Immunity Immunohistochemistry Impairment In Vitro Indium Infection Inflammatory Injection of therapeutic agent Injury Integrins Investigation Label Laboratories Leukocytes Ligands MYLK gene Magnetic Resonance Imaging Measures Medicine Microglia Modeling Modification Monomeric GTP-Binding Proteins Mus Myosin Light Chain Kinase Nerve Degeneration Neurodegenerative Disorders Neuroglia Neuronal Injury Neurons Neuropathogenesis Oligodendroglia Pathway interactions Pattern Penetration Permeability Pharmaceutical Preparations Physiological Physiology Process Program Research Project Grants Property Protein Chemistry Proteins RANTES Reaction Rodent Secondary to Side Site Specificity Stem cell transplant Stem cells Stromal Cell-Derived Factor 1 System Techniques Therapeutic Tight Junctions Tissues Toxin Trauma Virus Work adherent junction astrogliosis base bioimaging brain tissue cell motility chemokine chemokine receptor dentate gyrus design gliogenesis in vivo injury and repair iron oxide lateral ventricle macrophage migration monocyte monolayer mouse model nanoformulation nanomedicine nanoparticle nanotoxicology nerve stem cell neurogenesis neuroinflammation neuronal cell body neuropathology neuroprotection neurotoxicity novel therapeutic intervention olfactory bulb particle postnatal prevent programs regenerative relating to nervous system repaired research study response response to injury rho GTP-Binding Proteins single photon emission computed tomography synaptogenesis

项目摘要

While blood brain barrier (BBB) impairment is a critical feature of HIV-1 neuropathogenesis, the BBB also serves as a conduit for therapeutics brain delivery. How this intersects with BBB pathophysiology is the focus of the current project. It is a now well-established fact that neural progenitor cells (NPC) dynamically contribute to neuro- and gliogenesis in the postnatal brain and are being developed in this program grant (project 1, J. Zheng). In response to injury, infection, or neurodegeneration, progenitor cells migrate toward zones of tissue damage. Chemokines produced in association with neuroinflammatory responses likely act as chemoattractants for neural progenitors during brain injury. Whether NPC cross the BBB from blood remains unclear. We propose that systemic NPC can migrate across the BBB and promote neuroprotection while attenuating neuroinflammation in HIV-1 encephalitis (HIVE). We will study mechanisms governing NPC migration and their effect on the BBB using the pathophysiologically relevant assumption of chemokine overproduction in neuroinflammation. We will investigate how migration across the BBB alters how NPC differentiate into neurons and glia and the effects of NPC on the BBB from within the brain. Strategies in this program grant are being developed that enable a broad spectrum of anti-retroviral and adjunctive medicines for HIV-1 to be packaged into nanoparticles (NP; project 2, H. Gendelman). These can be taken by leukocytes and transported into areas of active neuroinflammation. While being an attractive specific way to facilitate anti-retroviral or anti-inflammatory drug delivery, it is currently unknown how NP-containing leukocytes affect BBB function during migration or from the 'brain' side of the barrier and perhaps even more importantly how they affect neuronal and glial integrity. Therefore, we will address the pathways and nanotoxicology for migration of macrophages across BBB with drug laden NP. We will evaluate the cell's ability to move and affect the integrity and function of the BBB and to affect diseaserelated neuropathology. These cell-based novel therapeutic approaches are interdisciplinary and show ynergy amongst the projects (NPC project 1, J. Zheng and NP-delivery of drugs project 2, H. Gendelman) with our own established expertise in BBB models. Importantly, three diverse animal models for HIVE will be employed to validate in vitro observations using in vivo imaging techniques allowing assessment of BBB integrity, neuronal injury, and neuroinflammation.

尽管血脑屏障（BBB）损伤是HIV-1神经病发生的关键特征，但BBB也充当治疗脑递送的管道。这如何与BBB病理生理学相交是重点当前项目。神经祖细胞（NPC）动态的事实是现在一个公认的事实在产后大脑中有助于神经和神经胶质发生，并正在该计划授予中开发（项目1，J。Zheng）。响应损伤，感染或神经变性，祖细胞迁移到组织损伤的区域。与神经炎症反应相关的趋化因子可能作用作为脑损伤期间神经祖细胞的趋化因子。 NPC是否从血液中越过BBB 仍然不清楚。我们建议系统性NPC可以跨BBB迁移并促进神经保护性在衰减HIV-1脑炎（Hive）中神经炎症的同时。我们将学习使用与病理生理相关的NPC迁移的机制及其对BBB的影响假设神经炎症中趋化因子过量产生。我们将调查如何迁移 BBB改变了NPC如何区分神经元和神经胶质以及NPC对BBB的影响脑。正在开发该计划赠款中的策略，以实现广泛的抗逆转录病毒将HIV-1包装到纳米颗粒中的辅助药物（NP；项目2，H。Gendelman）。这些可以用白细胞采用，并运输到活跃的神经炎症区域中。同时成为一个有吸引力的特定方法来促进抗逆转录病毒或抗炎药的递送，目前尚不清楚含NP的白细胞在迁移期间或障碍物的“大脑”一侧如何影响BBB功能也许更重要的是它们如何影响神经元和神经胶质完整性。因此，我们将解决巨噬细胞在BBB迁移的途径和纳米毒理学，并用药物为NP。我们将评估细胞移动和影响BBB的完整性和功能的能力并影响疾病神经病理学。这些基于细胞的新型治疗方法是跨学科的，并显示 Ynergy在项目中（NPC项目1，J。Zheng和NP Delivery of Drugs Project Project 2，H。 Gendelman）具有我们自己既定的BBB模型专业知识。重要的是，三种不同的动物模型对于Hive，将使用体内成像技术验证体外观察评估BBB完整性，神经元损伤和神经炎症。