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The role of lymphatic clearance in brain TB

淋巴清除在脑结核中的作用

基本信息

批准号：
10617380
负责人：
Matyas Sandor
金额：
$ 40.69万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-15 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10617380
关键词：
Acceleration Affect Alzheimer&apos s Disease Anti-Bacterial Agents Antibacterial Response Antigens Antimycobacterial Agents Autoimmune Diseases Bacterial Infections Binding Brain Brain Drains Brain Pathology Cell Communication Cell physiology Cells Central Nervous System Central Nervous System Infections Central Nervous System Tuberculosis Cerebral Edema Cerebrospinal Fluid Cerebrum Cervical lymph node group Complex Data Dendritic Cells Disease Disease Outcome Disease model Dorsal Drainage procedure Dura Mater Edema Encephalitis Endothelial Cells Experimental Autoimmune Encephalomyelitis Foundations Granuloma Homeostasis Human ITGAX gene Immune Immune response Immunity Immunologic Surveillance Impaired cognition In Situ Infiltration Inflammation Inflammatory Inflammatory Response Intercellular Fluid Lesion Liquid substance Longitudinal Studies Lung Lymphangiogenesis Lymphatic Lymphatic System Lymphatic clearance Lymphoid Macrophage Mediating Meningeal Meninges Modeling Multiple Sclerosis Mus Mycobacterium Infections Nerve Degeneration Outcome Parkinson Disease Pathogenesis Pathogenicity Pathology Physiology Play Production Proteins Publishing Regulation Regulatory Pathway Reporting Research Resolution Role Route Sculpture Severities Source Structure of choroid plexus System T-Lymphocyte Testing Therapeutic Tissues Traumatic Brain Injury Tuberculosis Tyrosine Kinase Inhibitor VEGFC gene Vascular Endothelial Growth Factor C Vascular Endothelial Growth Factor Receptor-3 Waste Management autoimmune inflammation brain parenchyma cribriform plate immunoregulation interest lymph nodes lymphatic circulation lymphatic drainage lymphatic vessel mortality mouse model mycobacterial neuroinflammation nonhuman primate novel novel therapeutic intervention novel therapeutics response trafficking tuberculosis treatment uptake wasting

项目摘要

PROJECT SUMMARY/ABSTRACT Brain tuberculosis (TB), the most severe form of tuberculosis, is associated with a complex inflammatory response, tissue damage and cerebral edema. Typically, management of fluid, waste, and immune- surveillance in the periphery is performed by tissue infiltrating lymphoid vessels. While the brain parenchyma does not have lymphoid vessels, recent research has identified that brain fluids (cerebrospinal fluid and interstitial fluid) are collected by meningeal and cribriform lymphoid vessels surrounding the brain, which are crucial for waste clearance and tissue homeostasis in the CNS. It has been shown that inhibition of lymphatic transport accelerates disease pathology and cognitive decline in Alzheimer’s disease, traumatic brain injury, and Parkinson’s disease, but little is known about the potential modulatory role of lymphoid vessels in CNS tuberculosis. Recently we reported that autoimmune inflammation induces lymphangiogenesis at the cribriform plate through the production of VEGFC from inflammatory dendritic cells. Functionally, the induction of new lymphoid vessels upregulates immunoregulatory molecules, and blocking new lymphoid vessel formation has consequences in regulating the severity of the autoimmune disease. In this proposal, we will test how CNS tuberculosis affects meningeal and cribriform lymphoid vessels formation and consequently, their fluid and cell draining function (Aim 1) To understand the impacts on immune-surveillance, we will study how CNS mycobacterial tuberculosis (Mtb) infection alters the expression of immune regulatory molecules on draining lymphoid vessels and how these lymphoid vessels modify brain-derived dendritic cells and their ability to influence downstream T cell priming in the lymph node (Aim 2). Lastly, we will use agents that block or promote lymphangiogenesis to test how brain inflammation, bacterial load, dissemination, and anti-bacterial immunity are affected by alterations of brain drainage with the hope of decreasing CNSTB associated pathologies (Aim 3). CNS tuberculosis is one of the most common bacterial infections of the brain with high mortality with a pressing need for new therapies, and these studies will lead to novel therapeutic strategies in CNSTB. The objectives of this proposal are (1) to test whether infiltrating or resident immune cells produce VEGFC that contributes to cribriform plate-associated, dorsal meningeal, or basal meningeal lymphangiogenesis during central nervous system tuberculosis (CNSTB) (Aim 1); to define cellular and bacterial interaction between Mtb- infected dendritic cells, Mtb, and lymphoid endothelial cells (LECs) (Aim 2); and to understand the translational value of lymphangiogenesis regulators on CNSTB pathogenesis, bacterial control, anti-bacterial responses, and bacterial dissemination (Aim 3). These studies will lead to a new aspect of brain TB pathology and reveal novel information comparing lymphatic vessel responses and brain drainage in different brain inflammations. These studies' long- term objective is to define how the lymphatic system represents a novel target in combating CNSTB.

项目总结/文摘