Project 5

项目5

• 批准号: 9924577
• 负责人: Bibhuti Bhusan Mishra
• 金额: $ 28.79万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2021-08-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924577
• 关键词: Acute; Agonist; Alzheimer' s Disease; Anti-Inflammatory Agents; Antigen-Presenting Cells; Antigens; Antiinflammatory Effect; Autoimmune Diseases; Brain; Cell physiology; Cells; Central Nervous System Infections; Cestoda; Chronic; Clinical; Clinical Trials; Cognition Disorders; Communities; Dementia; Development; Disease; Endothelial Cells; Environment; Galactosamine; Galactose; Galactose Binding Lectin; Glucosamine; Glycoproteins; Helminths; Human; Immune; Immune System Diseases; Immune response; Immunity; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory Response Pathway; Innate Immune System; Kinetics; Larva; Lectin Receptors; Light; Mediating; Mental Depression; Mental disorders; Mesocestoides; Microglia; Molecular; Multiple Sclerosis; Mus; Myelogenous; Myeloid Cells; Nerve Tissue; Neuraxis; Neurocysticercosis; Parasites; Parasitic infection; Pathologic; Pathology; Pharmaceutical Preparations; Phenotype; Physiologic pulse; Play; Polysaccharides; Population; Production; Psyche structure; Regulation; Role; Schizophrenia; Severity of illness; Shapes; Stimulus; Streptococcus suis; Stroke; Surface; Survival Rate; Taenia solium; Testing; Therapeutic; Tissues; Trichuris; United States; cell type; chronic infection; cytokine; design; differential expression; egg; helminth infection; immunopathology; immunoregulation; macrophage; migration; mouse model; multiple sclerosis patient; neuroinflammation; neuropathology; neutrophil; novel; novel strategies; pathogen; public health relevance; receptor; response; success; therapeutic target; tissue repair; trafficking; wound healing

SUMMARY: Inflammatory disorders can be triggered by overactive immune responses directed against host/self tissues. Indeed, neuroinflammation-associated disorders such as multiple sclerosis and stroke can be triggered and/or exacerbated by overactive immune responses against nervous tissues. It is now evident that not only cognitive disorders, but classic mental diseases such as schizophrenia and depression, are related to neuroinflammation. It is thus remarkable that infection with parasitic helminths (worms) suppresses inflammation in a variety of immune disorders. Ongoing clinical trials using worm egg in patients with multiple sclerosis are showing promising results. Hence, an understanding of helminth immunoregulatory mechanisms is likely to have enormous impact on novel strategies against inflammatory disorders. In this light, the regulation of inflammatory responses is mainly mediated via the innate immune system through antigen-presenting cells (APC) such as macrophages (M�) and microglia (MG). The functional phenotypes of MG and M� vary in response to external stimuli these cells receive through a wide variety of surface receptors. It is thought that worms or their products induce alternatively activated macrophages (AAM) that dampen inflammation and promotes tissue repair. We and others have recently documented that alternatively activated M� (AA-M�) and MG (AA-MG) have the capacity to dampen host inflammatory responses and promote wound healing and tissue repair in certain chronic neuroinflammation-related diseases. In a mouse model of neurocysticercosis (NCC) we demonstrated that AAMs are essential in containing neuropathology and disease severity. Additionally, consistent with human NCC, highly antigenic tegument galactose/ galactosamine and glucosamine containing glycan molecules of the parasite are released and taken up by host cells in the CNS environment. As lectin receptors (LRs) are the major receptors for recognition of glycan antigens, a study of their role in AA-M� and AA-MG functions in the CNS during NCC are important for understanding how NCC and neuropathological conditions can be clinically controlled. We hypothesize that glycan antigens released by parasites will lead to differential expression of specific host LRs which will play a critical role in the development and trafficking of AAM into the CNS, expression of effector molecules, and regulation of CNS immunopathology. To test this hypothesis we propose 3 specific aims. (Aim 1) Determine the expression, kinetics, and cellular distribution of LRs during NCC by focusing on Galectin-7, Galectin-9, and SIGNR1. (Aim 2) Identify the role of targeted LRs in AA-M� and AA-MG development, migration and functions. (Aim 3) Elucidate the significance of targeted LRs in regulating AA-M� and AA-MG mediated control of CNS immunopathogenesis in murine NCC. Our findings in the planned studies are expected to provide new directions and approaches to manipulate AA-M� and AA-MG function to suppress inflammation in a variety of inflammatory disorders, including but not limited to CNS inflammatory diseases.

摘要： 针对人的免疫反应过度活跃可引发炎症性疾病 宿主/自身组织。事实上，多发性硬化症等与神经炎症相关的疾病 过度活跃的免疫反应可触发和/或加重中风 神经组织。现在很明显，不仅认知障碍，而且经典的精神疾病 如精神分裂症和抑郁症，都与神经炎症有关。因此，这是值得注意的 感染寄生虫(蠕虫)可抑制多种免疫系统的炎症。 精神错乱。正在进行的对多发性硬化症患者使用虫卵的临床试验显示 结果令人振奋。因此，了解蠕虫的免疫调节机制是可能的。 对抗炎性疾病的新战略产生巨大影响。从这个角度来看， 炎症反应的调节主要是通过先天免疫系统来实现的 抗原提呈细胞，如巨噬细胞(M�)和小胶质细胞(MG)。功能界别 MG和M-�的表型因这些细胞通过A细胞接受外界刺激而不同 各种各样的表面感受器。人们认为蠕虫或它们的产物可以交替诱导 激活的巨噬细胞(AAM)，抑制炎症，促进组织修复。我们和 其他人最近发现，交替激活的M�(AA-M�)和MG(AA-MG) 有能力抑制宿主的炎症反应，促进伤口愈合和 某些慢性神经炎症相关疾病的组织修复。在小鼠模型中 脑囊虫病(NCC)我们证明了AAM在包含 神经病理学和疾病严重程度。此外，与人类NCC一致，高度抗原性 半乳糖/半乳糖/氨基葡萄糖和氨基葡萄糖 寄生虫在中枢神经系统环境中被宿主细胞释放和摄取。作为凝集素受体 (LR)是识别多糖抗原的主要受体，关于它们在AA-M�中作用的研究 和AA-MG在NCC期间中枢神经系统的功能对于理解NCC和 神经病理情况在临床上是可以控制的。我们假设糖链抗原 由寄生虫释放会导致特定宿主LR的差异表达，这将发挥 AAM在发展和转运到中枢神经系统中的关键作用，效应分子的表达 分子和中枢神经系统免疫病理的调节。为了检验这一假设，我们提出了3个 明确的目标。(目标1)确定LRs的表达、动力学和细胞分布 NCC通过关注Galectin-7、Galectin-9和SIGNR1。(目标2)确定目标的作用 LR在AA-M�和AA-MG中的发育、迁移和功能。(目标3)澄清 靶向受体在调节AA-M�和AA-MG介导的中枢神经系统调控中的意义 小鼠NCC的免疫发病机制。我们在计划中的研究中的发现有望 为调控AA-M�和AA-MG功能抑制提供新的方向和途径 各种炎症性疾病中的炎症，包括但不限于中枢神经系统 炎症性疾病。