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Project 5

项目5

基本信息

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
项目类别：
财政年份：
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&apos 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

项目摘要

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.

简介: