Impact of human anti-NMDA receptor antibodies on glutamate receptor signaling, calcium mobilization, and hippocampal neuronal circuits in autoimmune encephalitis

人抗 NMDA 受体抗体对自身免疫性脑炎中谷氨酸受体信号传导、钙动员和海马神经元回路的影响

• 批准号: 10019421
• 负责人: David Roger Benavides
• 金额: $ 19.13万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10019421
• 关键词: Acute; Address; Affect; Agitation; Alzheimer' s Disease; Animal Model; Antibodies; Area; Autoimmune encephalitis; Autonomic Dysfunction; Behavioral; Binding; Biochemical; Brain; Brain Diseases; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Cell Surface Proteins; Cells; Cessation of life; Clinical; Cognitive; Coma; Complex; Cyclic AMP-Dependent Protein Kinases; Data; Development; Development Plans; Disease; Doctor of Medicine; Doctor of Philosophy; Drug usage; Educational workshop; Elements; Encephalitis; Epilepsy; Fc Receptor; Functional disorder; Future; Genetic Predisposition to Disease; Glutamate Receptor; Glutamates; Goals; Hippocampus (Brain); Human; Image; Immune; Immune response; Immune system; Individual; Instruction; Intuition; Knowledge; Lead; Learning; Left; Link; Maryland; Measures; Mediating; Membrane Proteins; Memory; Memory impairment; Mentors; Mentorship; Microscopy; Molecular; Morbidity - disease rate; Motor; Movement Disorders; Multiple Sclerosis; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuraxis; Neurodegenerative Disorders; Neurology; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Neurosciences; Neurosciences Research; Neurotransmitter Receptor; Outcome; Paralysed; Pathogenicity; Pathway interactions; Patients; Performance; Phosphoric Monoester Hydrolases; Phosphorylation; Physicians; Positioning Attribute; Principal Investigator; Program Development; Protein Kinase; Protein-Serine-Threonine Kinases; Proteomics; Psychotic Disorders; Public Health; Receptor Signaling; Regulation; Research; Research Personnel; Research Project Grants; Research Training; Resources; Rodent; Scientist; Seizures; Severities; Signal Pathway; Signal Transduction; Site; Surface; Survivors; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; System; Technology; Time; Training; Translational Research; United States National Institutes of Health; Universities; Work; calmodulin-dependent protein kinase II; career; career development; cognitive task; disability; experience; high risk; immunoregulation; in vivo; in vivo imaging; innovation; insight; live cell microscopy; medical schools; memory process; mortality; nervous system disorder; neural network; neurobehavioral; neuroimmunology; neuronal circuitry; neuroregulation; neurotransmission; new therapeutic target; novel; novel therapeutics; object recognition; postsynaptic neurons; professor; protein complex; release of sequestered calcium ion into cytoplasm; targeted treatment; trafficking; translational neuroscience; treatment strategy

This is a proposal for a five year research career development program focused on the study of human antibodies binding to neuronal cell surface proteins in autoimmune encephalitis. The goal is to gain understanding of the pathophysiology of autoimmune encephalitis and identify novel targets for therapy in neurological disease. The principal investigator, David R. Benavides, M.D., Ph.D., is an Assistant Professor of Neurology at University of Maryland School of Medicine. My long term career goal is to become an independent investigator in translational research focused on immune regulation of neural function in neurological disease. To accomplish this goal, I propose a research project and training plan in proteomics, advanced live cell microscopy, and in vivo miniscope technology, which is integral to addressing the central research question posed here. The research project builds on my previous research in signal transduction and molecular neuroscience and clinical experience in neuroimmunology and integrates innovative approaches in areas of expertise represented by my mentor team at University of Maryland School of Medicine. I propose a comprehensive development plan, combining didactic instruction overseen by my mentors, formal coursework, applied training experiences with individual advisors, and participation in seminars and workshops. The proposed project and development plan will position me with a unique skillset that will enable me to transition to independence as a physician-scientist in translational neuroscience research. Encephalitis is a brain disease with significant morbidity and mortality. Anti-NMDA receptor (NMDAR) encephalitis is the most common form of autoimmune encephalitis and accounts for nearly 4% of all cases of encephalitis. Excitatory synaptic transmission and plasticity in the central nervous system are governed, in part, by a class of glutamate neurotransmitter receptors known as NMDARs. NMDAR dysfunction can cause psychosis, impaired memory, agitation, movement disorders, seizures, and coma and may result from many conditions, such as drug use, genetic predisposition, and antibody targeting (e.g., anti-NMDAR encephalitis). The effects of NMDAR antibodies on brain function in autoimmune encephalitis remain incompletely defined. My preliminary data show that NMDAR antibodies alter neuronal signaling and neuronal activity in primary rodent dissociated neuron cultures. How exactly NMDAR antibodies do this in anti-NMDAR encephalitis is a question that this proposal begins to address. Specifically, the aims of the proposal are: 1) define the effects of NMDAR antibodies on glutamate receptor signaling pathways, 2) determine the effects of NMDAR antibodies on neuronal calcium mobilization, and 3) determine the effect of NMDAR antibodies on hippocampal neuronal circuits in vivo. Our long term goal of this work is to elucidate the effects of human NMDAR antibodies in autoimmune encephalitis to advance novel therapeutics for neurological disease.

这是一个五年的研究生涯发展计划的建议，重点是研究人类抗体