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：
10522419
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/10522419
关键词：
Affect Alzheimer&apos s Disease Anti-Bacterial Agents Antibacterial Response Antigens Autoimmune Diseases Bacterial Infections Binding Brain Brain Drains Brain Pathology Cell physiology Cells 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 Lead Lesion Liquid substance Longitudinal Studies Lung Lymphangiogenesis Lymphatic Lymphatic System Lymphatic clearance Lymphoid Mediating Meningeal Meninges Modeling Multiple Sclerosis Mus Mycobacterium Infections Nerve Degeneration Neuraxis 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 Receptor-3 Waste Management autoimmune inflammation brain parenchyma cribriform plate immunoregulation interest lymph nodes lymphatic circulation lymphatic drainage lymphatic vessel macrophage 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.

项目摘要/摘要脑结核（TB）是结核病的最严重形式，与复杂的炎症有关反应，组织损伤和脑水肿。通常，流体，废物和免疫的管理周围的监测是通过组织浸润淋巴管进行的。而大脑实质没有淋巴管，最近的研究表明脑液（脑脊液和通过脑膜和丝布状淋巴管收集间隙液）中枢神经系统中的废物清除和组织稳态至关重要。已经表明抑制淋巴运输加速了阿尔茨海默氏病，创伤性脑损伤的疾病病理和认知能力下降，和帕金森氏病，但对CNS中淋巴管的潜在调节作用知之甚少结核。最近，我们报道自身免疫性感染会影响筛状的淋巴管发生通过炎性树突状细胞产生VEGFC的板块。在功能上，新的诱导淋巴管上调免疫调节分子，并阻断新的淋巴管的形成调节自身免疫性疾病严重程度的后果。在此建议中，我们将测试CNS 结核病会影响脑膜和环形淋巴管的形成，因此，它们的液体和细胞排水功能（AIM 1）以了解对免疫监视的影响，我们将研究如何 CNS分枝杆菌结核病（MTB）感染改变了免疫调节分子在上的表达排干淋巴管以及这些淋巴管如何修饰脑衍生的树突细胞及其能力影响下游T细胞在淋巴结中的启动（AIM 2）。最后，我们将使用阻止或促进淋巴管生成以测试脑感染，细菌负荷，传播和抗细菌免疫力受到大脑流量改变的影响，希望减少CNSTB相关病理（目标3）。中枢神经系统结核病是大脑最常见的细菌感染之一对新疗法的迫切需求的死亡率，这些研究将导致新的治疗策略 CNSTB。该提案的目标是（1）测试浸润或常驻免疫球产生的VEGFC 这有助于环形板板相关，背脑膜或基本脑膜淋巴管发生中枢神经系统结核病（CNSTB）（AIM 1）；定义MTB-之间的细胞和细菌相互作用感染的树突状细胞，MTB和淋巴内皮细胞（LEC）（AIM 2）；并了解翻译淋巴管生成调节剂对CNSTB发病机理，细菌控制，抗细菌反应的值，和激进的传播（目标3）。这些研究将导致大脑结核病病理的新方面，并揭示比较的新信息不同大脑注射的淋巴管反应和大脑引流。这些研究长期术语目标是定义淋巴系统如何代表对抗CNSTB的新目标。