Lymphangiogenesis in chronic brain infection

慢性脑感染中的淋巴管生成

• 批准号: 10593252
• 负责人: TAJIE H. HARRIS
• 金额: $ 43.46万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10593252
• 关键词: Affect; Alzheimer' s Disease; Biological Process; Brain; Brain Edema; C57BL/6 Mouse; Cells; Central Nervous System Infections; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Cervical; Cessation of life; Characteristics; Chronic; Coma; Cyst; Defect; Dependovirus; Development; Drainage procedure; Edema; Encephalitis; Flow Cytometry; Fluid Balance; Growth; Growth Factor; Histologic; Homeostasis; Immune; Immune response; Infection; Infiltration; Inflammation; Inflammation Mediators; Intervention; Intracranial Hypertension; Intracranial Pressure; Ischemia; Lead; Length; Liquid substance; Lymph; Lymphangiogenesis; Lymphatic; Lymphatic System; Measures; Meningeal; Meningeal lymphatic system; Meninges; Meningitis; Modeling; Morbidity - disease rate; Multiple Sclerosis; Mus; Natural regeneration; Neuraxis; Parasites; Peripheral; Population; Proteins; Resolution; Seizures; Severities; Site; Stains; Swelling; Testing; Therapeutic; Therapeutic Effect; Tissues; Toxoplasma gondii; Toxoplasmosis; Tracer; Traumatic Brain Injury; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor D; adeno-associated viral vector; brain parenchyma; chronic infection; cranium; immune clearance; improved; insight; lymphatic vasculature; lymphatic vessel; mortality; neuroinflammation; novel therapeutics; pathogen; prevent; receptor; response; restoration; therapeutic development; tool; toxoplasmic encephalitis

PROJECT SUMMARY Infections of the brain cause significant morbidity and mortality. During infections, the brain can swell in response to direct damage by a pathogen and as a consequence of the immune response. The brain has a limited ability to expand within the skull, leading to increases in intracranial pressure that can cause seizures, coma, or even death due to brain herniation. In many tissues, lymphatic vessels remove excess fluid and immune cells to control swelling and resolve inflammation. The presence of lymphatic vessels in the central nervous system was described in 2015 and suggests that fluid and immune cells may exit the CNS via this meningeal lymphatic network. In our studies examining the immune response to Toxoplasma gondii, a parasite that causes chronic encephalitis in C57BL/6 mice, we find increased intracranial pressure and edema in the brain coincident with a strong immune response to the parasite. Subsequently, we also observe that the meningeal lymphatics begin to expand in length and complexity, consistent with lymphangiogenesis. The robust meningeal lymphangiogenesis we observe is associated with a resolution of elevated intracranial pressure. We hypothesize that the expansion of the lymphatic vessels allows for more fluid to leave the meninges which ameliorates elevated intracranial pressure and for immune cells to exit the CNS reducing meningitis. We will test these hypotheses in two aims: Aim 1. How does the blockade or promotion of meningeal lymphangiogenesis affect fluid homeostasis in the infected brain? Aim 2. How is inflammation within the meninges affected by the expansion of the local lymphatic vasculature? We will utilize two key tools to prevent and promote meningeal lymphangiogenesis. We will prevent lymphatic growth by targeting the growth factors VEGF-C and VEGF-D using a soluble decoy receptor (sVEGRF3) delivered to the meninges using an AAV. Conversely, we will treat mice with and AAV that expresses VEGF-C to expand the CNS lymphatics to understand if enhanced lymphangiogenesis has a therapeutic effect. We will measure fluid dynamics using tracer studies and measure any impact on tissue edema or intracranial pressure. We will also examine how the immune response in the meninges and parasite burden are affected by local the promotion or block of CNS lymphangiogenesis. Together these studies will examine how the newly discovered meningeal lymphatic vessels function during CNS infection to maintain fluid homeostasis and control inflammation. The induction of lymphangiogenesis in the meninges may have immense therapeutic potential as there are limited interventions for chronic elevations in intracranial pressure due to persistent CNS infections.

项目摘要 脑感染导致显著的发病率和死亡率。在感染过程中，大脑会膨胀 直接受到病原体的伤害，并作为免疫反应的结果。大脑的能力有限 在颅骨内膨胀，导致颅内压升高，可能导致癫痫发作，昏迷，甚至 死于脑疝在许多组织中，淋巴管清除多余的液体和免疫细胞，以控制 消肿消炎。中枢神经系统中淋巴管的存在， 在2015年描述，并表明液体和免疫细胞可以通过这个脑膜淋巴管离开CNS 网络在我们的研究中，检测了对弓形虫的免疫反应，弓形虫是一种寄生虫， 在C57 BL/6小鼠的脑炎中，我们发现颅内压增加和脑水肿与脑水肿的发生一致。 对寄生虫有很强的免疫反应随后，我们还观察到脑膜炎开始 长度和复杂性增加，与淋巴管生成一致。强大的脑膜淋巴管生成 我们观察到与颅内压升高的消退有关。我们假设膨胀 淋巴管的扩张允许更多的液体离开脑膜，这改善了颅内压升高， 压力和免疫细胞退出中枢神经系统减少脑膜炎。我们将在两个目标中检验这些假设： 目标1。脑膜淋巴管生成的阻断或促进是如何影响脑脊髓液的稳态的？ 感染的大脑目标二。脑膜内的炎症如何受到局部淋巴管扩张的影响 脉管系统？我们将利用两个关键工具来预防和促进脑膜淋巴管生成。我们会阻止 通过使用可溶性诱饵受体靶向生长因子VEGF-C和VEGF-D的淋巴管生长 使用AAV将sVEGRF 3（sVEGRF 3）递送至脑膜。相反，我们将用表达 VEGF-C扩大中枢神经系统免疫学，以了解增强的淋巴管生成是否具有治疗作用。 我们将使用示踪剂研究测量流体动力学，并测量对组织水肿或颅内 压力我们还将研究脑膜中的免疫反应和寄生虫负荷如何受到 局部促进或阻断CNS淋巴管生成。这些研究将共同探讨新的 发现脑膜淋巴管在中枢神经系统感染期间起着维持体液平衡和控制 炎症脑膜中淋巴管生成的诱导可能具有巨大的治疗潜力， 对于由于持续性CNS感染引起的颅内压慢性升高的干预有限。