Mechanisms of Caspr2 antibodies

描述(由申请人提供)：这个K08职业发展奖将促进PI发展成为一名临床科学家，拥有专注于抗体介导的神经疾病的独立研究计划。这项拨款中的科学计划专注于一种由抗Caspr2抗体定义的疾病，Caspr2是一种在中枢和外周神经系统轴突上表达的蛋白质。PI和他的同事最近报告说，以前被认为是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等人，2010年；Lancaster等人，2011年)。抗Caspr2抗体阳性的患者通常有脑炎和/或周围神经兴奋性亢进。虽然Caspr2抗体阳性的患者对免疫治疗有反应，但大多数人都有持续性的认知障碍。编码Caspr2的基因突变与自闭症和其他智力障碍有关。在5年的获奖期内，将探索抗Caspr2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Caspr2蛋白上的区域，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探讨Caspr2抗体对中枢和外周神经系统轴突的影响。目标3将研究保护神经轴突免受自身抗体攻击的因素。这将改善对这些患者的治疗，并更好地了解Caspr2的功能。PI将由三位拥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)。这项科学工作将在谢尔和巴利斯-戈登博士的实验室完成，这两个实验室占据了宾夕法尼亚大学邻近的空间。一个培训计划，以协助私人投资发展新的研究技能是这项申请不可或缺的一部分。这些技能将通过具体的课程作业，通过他的导师进行的“动手”培训，以及通过在会议上介绍他的科学工作来获得。具体的科学技能包括免疫学、自身免疫性疾病、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。由于这一项目既涉及人类受试者，也涉及实验动物，因此在这两个领域涉及的伦理问题方面的具体培训都纳入了培训计划。

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.