Project 5

项目5

• 批准号: 9273572
• 负责人: Bibhuti Bhusan Mishra
• 金额: $ 24.75万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9273572
• 关键词: Acute; Agonist; Alzheimer' s Disease; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Antigens; 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; Stroke; Surface; Survival Rate; Taenia solium; Testing; Therapeutic; Tissues; Trichuris; United States; Wound Healing; cell type; cytokine; design; differential expression; egg; 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

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.

概括： 炎症性疾病可以通过针对的过度活跃的免疫调查引发 宿主/自我组织。实际上，神经炎症相关的疾病，例如多发性硬化症 并且可以通过过度活跃的免疫调查触发和/或加剧中风 神经组织。现在有证据表明不仅认知障碍，而且经典精神疾病 诸如精神分裂症和抑郁症与神经炎症有关。因此，这很了不起 寄生虫的感染（蠕虫）抑制了各种免疫的感染 疾病。在多发性硬化症患者中使用蠕虫卵进行的正在进行的临床试验显示 有希望的结果。因此，可能是对蠕虫免疫调节机制的理解 对针对炎症性疾病的新型策略产生巨大影响。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介导的 抗原呈递细胞（APC），例如巨噬细胞（M？）和小胶质细胞（MG）。功能 Mg和M字的表型随着外部刺激的响应而异，这些细胞通过A接受 各种各样的表面受体。人们认为蠕虫或其产品会影响 该死的注射并促进组织修复的活化巨噬细胞（AAM）。我们和 其他人最近记录了激活的M€（aa-m？）和MG（AA-MG） 有能力托管炎症反应并促进伤口愈合和 某些慢性神经炎症相关疾病的组织修复。在鼠标模型中 神经囊肿（NCC）我们证明了AAM在包含 神经病理学和疾病的严重程度。另外，与人NCC一致，高度抗原 tegument半乳糖/半乳糖胺和葡萄糖含有含聚糖分子的葡萄糖分子 寄生虫在中枢神经系统环境中被宿主细胞释放并吸收。作为讲座的接收器 （LRS）是识别聚糖抗原的主要接收器，这是对它们在AA-M的作用的研究。 NCC期间CNS中的AA-MG功能对于了解NCC和 神经病理条件可以在临床上控制。我们假设是聚糖抗原 由寄生虫发布将导致特定宿主LR的差异表达，这将播放 在AAM进入中枢神经系统的发展和贩运中的关键作用，效应子的表达 分子和CNS免疫病理学的调节。为了检验这一假设，我们提出了3 具体目标。 （AIM 1）确定LRS期间LR的表达，动力学和细胞分布 通过关注Galectin-7，Galectin-9和Signr1，NCC。 （目标2）确定目标的作用 LRS中的AA-M？以及AA-MG的开发，迁移和功能。 （目标3）阐明 靶向LRS在调查AA-M€和AA-MG介导的CNS中的重要性 鼠NCC中的免疫致病发生。我们在计划研究中的发现有望 提供新的方向和方法来操纵AA-M？和AA-MG功能以抑制 多种炎症性疾病的炎症，包括但不限于CNS 炎症性疾病。