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Mechanisms of Caspr2 antibodies

Caspr2抗体的机制

基本信息

批准号：
9109066
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
项目类别：
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/9109066
关键词：
Adhesions Afferent Neurons Anatomy Antibodies Area Attention Autistic Disorder Autoantibodies Autoantigens Award Axon Binding Biological CNTNAP1 gene Cells Complement Complement Inactivators DNA Sequence Alteration Development Disease Encephalitis Epitopes Ethics Extracellular Domain Functional disorder Genes Genetic Glioma Grant Hand Health Hereditary Disease Histology Human Immune System Diseases Immunology Immunotherapy Impaired cognition Intellectual functioning disability K-Series Research Career Programs Knockout Mice Kv1.2&apos channel Laboratories Laboratory Animals Lead Leucine 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 cognitive disability disability glycosylation human subject improved meetings molecular domain nervous system disorder neurophysiology novel novel therapeutics programs protein protein interaction research study skills

项目摘要

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.

描述（由申请人提供）：K08职业发展奖将促进PI发展成为具有独立研究项目的临床科学家，专注于抗体介导的神经系统疾病。这项拨款的科学项目主要关注一种由Caspr2抗体定义的疾病，Caspr2是一种在中枢和周围神经系统轴突上表达的蛋白质。PI及其同事最近报道，先前归因于钾通道的自身抗体实际上针对两个钾通道相关蛋白LGI1和CASPR2 （Lai et al., 2010; Lancaster et al., 2011）。Caspr2抗体患者通常有脑炎和/或周围神经亢奋。虽然Caspr2抗体对免疫治疗有反应，但大多数患者存在持续性认知障碍。编码Caspr2基因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Caspr2抗体的机制，以指导新疗法的研究，并更好地了解相关遗传疾病。目的1将探索抗体靶向Caspr2蛋白上的结构域，以及这些抗体如何破坏Caspr2与其他神经元蛋白的相互作用。目的2将探讨Caspr2抗体对中枢和周围神经系统轴突的影响。第三部分将探讨保护神经轴突免受自身抗体侵害的因素。这将改善这些患者的治疗方法，并更好地了解Caspr2的功能。PI将由三位具有完成该项目所需的不同专业领域的导师指导：Joseph Dalmau博士（抗体介导的神经系统疾病），Steven S. Scherer博士（周围神经解剖学和组织学）和Rita Balice-Gordon博士（突触生理学和解剖学）。科学工作将在博士的实验室完成。Schere和Balice-Gordon，它们在宾夕法尼亚大学占据相邻的空间。协助PI发展新的研究技能的培训计划是该应用程序的一个组成部分。这些技能将通过具体的课程学习、导师的“动手”培训以及在会议上展示他的科学工作来获得。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、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动物，因此在这两个领域涉及的伦理问题的具体培训已纳入培训计划。