Mechanisms of Caspr2 antibodies

Caspr2抗体的作用机制

• 批准号: 8383911
• 负责人: ERIC LANCASTER
• 金额: $ 18.92万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8383911
• 关键词: Adhesions; Afferent Neurons; Anatomy; Antibodies; Area; Attention; Autistic Disorder; Autoantibodies; Autoantigens; Award; Axon; Binding; Biological; Cells; Cognitive; Complement; Complement Inactivators; Development; Disease; Encephalitis; Epitopes; Ethics; Extracellular Domain; Functional disorder; Gene Mutation; Genes; Genetic; Grant; Hand; Hereditary Disease; Histology; Human; Immune System Diseases; Immunology; Immunotherapy; Impaired cognition; Intellectual functioning disability; K-Series Research Career Programs; Knockout Mice; Kv1.2' channel; Laboratories; Laboratory Animals; Lead; Limbic Encephalitis; Location; Measures; Mediating; Membrane; Mentors; Molecular; Mus; Mutation; Nerve; Neuromuscular Junction; Neurons; Optics; Pain; Patients; Pennsylvania; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Physiology; Potassium; Potassium Channel; Proteins; Regulation; Reporting; Research; Role; Scientist; Seizures; Sensory; Septate; Series; Site; Spasm; Spinal Ganglia; Symptoms; Synapses; TAG-1 axonal glycoprotein; Testing; Training; Transfection; Universities; Voltage-Gated Potassium Channel; Wild Type Mouse; Work; base; contactin; disability; glycosylation; human LGI1 protein; human subject; improved; meetings; molecular domain; nervous system disorder; neurophysiology; novel; programs; protein protein interaction; research study; skills

DESCRIPTION (provided by applicant): This K08 career development award will facilitate the development of the PI into a clinician scientist with an independent research program focused on antibody mediated neurological disorders. The scientific program in this grant focuses on a disorder defined by antibodies to Caspr2, a protein expressed on axons in the central and peripheral nervous systems. The PI and his coworkers have recently reported that auto antibodies previously attributed to potassium channels actually target two potassium channel associated proteins, LGI1 and CASPR2 (Lai et al., 2010; Lancaster et al., 2011). Patients with antibodies to Caspr2 usually have encephalitis and/or peripheral nerve hyper-excitability. While patients with Caspr2 antibodies respond to immunotherapy, most have persistent cognitive disability. Genetic mutations in the gene encoding Caspr2 have been associated with Autism and other intellectual disabilities. During the 5 years of the award period, the mechanisms of antibodies to Caspr2 will be explored in order to guide research into new therapies, and to better understand the related genetic disorders. Aim 1 will explore the domains on the Caspr2 protein targeted by the antibodies and how these antibodies disrupt the interaction of Caspr2 with other neuronal proteins. Aim 2 will explore the effects of Caspr2 antibodies on central and peripheral nervous system axons. And Aim 3 will examine the factors protecting nerve axons from auto- antibodies. This will lead to improved treatments for these patients and better understanding of the functions of Caspr2. The PI will be guided by three mentors with distinct areas of expertise that are necessary to complete this project: Dr. Joseph Dalmau (antibody mediated disorders of the nervous system), Dr. Steven S. Scherer (peripheral nerve anatomy and histology) and Dr. Rita Balice-Gordon (synaptic physiology and anatomy). The scientific work will be completed in the laboratories of Drs. Schere and Balice-Gordon, which occupy adjacent space at the University of Pennsylvania. A training plan to assist the PI in developing new research skills is an integral part of this application. These skills will be acquired through specific course work, through "hands on" training by his mentors, and through presentation of his scientific work at meetings. Specific scientific skills include studies of immunology, auto-immune disorders, synaptic physiology and anatomy, and peripheral nerve anatomy and physiology. Since this project involves both human subjects and laboratory animals, specific training in the ethical concerns involved in both areas is integrated into the training plan. PUBLIC HEALTH RELEVANCE: Patients with auto antibodies to Caspr2 may have encephalitis (seizures, cognitive impairment) and/or peripheral nerve hyper excitability (resulting in debilitating muscle spasms). Genetic mutations in Caspr2 may cause autism and other intellectual disabilities. This project will explore the mechanisms of Caspr2 antibodies in order t find better therapies and to understand the role of Caspr2 in neuronal function.

描述（由申请人提供）：该K 08职业发展奖将促进PI发展成为临床科学家，其独立研究项目专注于抗体介导的神经系统疾病。这项资助的科学计划重点关注由Caspr 2抗体定义的疾病，Caspr 2是一种在中枢和外周神经系统轴突上表达的蛋白质。PI和他的同事最近报道了先前归因于钾通道的自身抗体实际上靶向两种钾通道相关蛋白LGI 1和CASPR 2（Lai et al.，2010;兰开斯特等人，2011年）。具有Caspr 2抗体的患者通常患有脑炎和/或外周神经过度兴奋。虽然携带Caspr 2抗体的患者对免疫疗法有反应，但大多数患者都有持续的认知障碍。编码Caspr 2的基因突变与自闭症和其他智力残疾有关。在5年的奖励期内，将探索Caspr 2抗体的机制，以指导新疗法的研究，并更好地了解相关的遗传疾病。目的1将探索抗体靶向的Caspr 2蛋白上的结构域，以及这些抗体如何破坏Caspr 2与其他神经元蛋白的相互作用。目的2探讨Caspr 2抗体对中枢和外周神经系统轴突的影响。目标3将检测保护神经轴突免受自身抗体侵害的因素.这将有助于改善这些患者的治疗方法，并更好地了解Caspr 2的功能。PI将由三位导师指导，他们具有完成本项目所需的不同专业领域：Joseph Dalmau博士（抗体介导的神经系统疾病），Steven S.谢勒（周围神经解剖学和组织学）和丽塔Balice-Gordon博士（突触生理学和解剖学）。科学工作将在Schere博士和Balice-Gordon博士的实验室完成，这两个实验室位于宾夕法尼亚大学的相邻空间。培训计划，以帮助PI在发展新的研究技能是本申请的一个组成部分。这些技能将通过具体的课程工作，通过他的导师的“动手”培训，并通过在会议上介绍他的科学工作获得。具体的科学技能包括免疫学，自身免疫疾病，突触生理学和解剖学，以及周围神经解剖学和生理学的研究。由于该项目涉及人类受试者和实验室动物，因此将这两个领域所涉及的伦理问题的具体培训纳入培训计划。 公共卫生关系：具有针对Caspr 2的自身抗体的患者可能患有脑炎（癫痫发作、认知障碍）和/或外周神经过度兴奋（导致癫痫发作）。 在使人衰弱的肌肉痉挛中）。Caspr 2的基因突变可能导致自闭症和其他智力残疾。本项目将探索Caspr 2抗体的作用机制，以找到更好的治疗方法，并了解Caspr 2在神经功能中的作用。