Role of the Kinesin KIF1A in Neurological Disease

人类驱动蛋白基因KIF 1A的突变导致多种神经缺陷。这种综合症有 由于这种疾病的罕见性，它的定义仍然很模糊。这项提案汇集了非常不同的， 但哥伦比亚大学医学院的温迪·钟博士的专业知识高度互补， 人类遗传性疾病; Richard Vallee博士，同样来自哥伦比亚，是Kif 1a在神经元中作用的专家 以及阿尔伯特·爱因斯坦医学院的阿恩·根纳里希博士，他是一位 马达蛋白生物物理学钟博士的实验室已经开发出临床和计算方法来编译 来自当地和世界各地患者的关于相关症状范围、严重程度和种类的信息 她的实验室称之为KAND KIF 1A相关神经疾病。这是一组异质性的严重神经退行性疾病，包括痉挛性截瘫、周围性瘫痪、 神经病、视神经萎缩、大脑和小脑萎缩、认知障碍和癫痫发作。的 条件可用。该项目的总体目标是 获得足够的临床信息，以了解KAND症状的全方位;确定如何 Kif 1a运动域中不同位点的突变影响临床结果;了解细胞和 发展的原因综合征;并确定小分子试剂来治疗它。目标1将是 根据快速增加的患者数据库定义KAND的自然史，并将临床 KIF 1A基因型的严重程度和进展率。目标2将是使用先进的单分子 生物物理和体内轴突运输方法，以确定分子和细胞的后果， Kif 1a突变目的3将使用Kif 1a突变小鼠来确定纵向和横截面 在模型生物体中的条件的影响，并更全面地测试BDNF在KAND中的作用， 小分子BDNF模拟物作为KAND治疗剂的价值。这些研究非常重要 原因有很多它们将极大地扩展我们识别和描述罕见 疾病他们将提供详细的了解运动蛋白相关疾病的分子基础。 他们将提供有关疾病进展和突变关系的广泛的新信息 现场预测而且，他们将利用我们对基因的新的分子和生理学见解， 开发靶向治疗的功能。 可能是致命的，目前没有治疗方法，

Mutations in the human kinesin gene KIF1A cause a variety of neurological defects. This syndrome has remained poorly defined because of the rarity of the condition. This proposal brings together the very different, but highly complementary expertise of Dr. Wendy Chung at Columbia University Medical School, a specialist in human genetic disease; Dr. Richard Vallee, also at Columbia, an expert in the role of Kif1a in neuronal development and physiology; and Dr. Arne Gennerich, at Albert Einstein College of Medicine, an expert in motor protein biophysics. Dr. Chung's lab has developed clinical and computational methods to compile information from patients locally and worldwide on the range, severity, and variety of symptoms associated with this condition, which her lab has termed KAND KIF1A Associated Neurological Disorders. This is a heterogeneous group of severe neurodegenerative conditions, including spastic paraplegia, peripheral neuropathy, optic nerve atrophy, cerebral and cerebellar atrophy, cognitive impairment, and seizures. The condition available. The over-all goals of this project are to obtain sufficient clinical information to understand the full-range of KAND symptoms; to determine how mutations at diverse sites within the Kif1a motor domain impact clinical outcome; to understand the cellular and developmental causes of the syndrome; and to identify small molecule reagents to treat it. Aim 1 will be to define the natural history of KAND based on a rapidly increasing patient database and correlate clinical severity and rate of progression with KIF1A genotype. Aim 2 will be to use advanced single molecule biophysical and in vivo axonal transport approaches to determine the molecular and cellular consequences of the Kif1a mutations. Aim3 will be to use Kif1a mutant mice to determine the longitudinal and cross-sectional effects of the condition in a model organism, and to test more completely the role of BDNF in KAND and the value of small molecule BDNF mimetics as KAND therapeutic agents. These studies are of great importance for a number of reasons. They will dramatically extend our capability to identify and characterize rare diseases. They will provide detailed insight into the molecular basis of a motor protein-associated disease. They will provide extensive new information on the progression of the disease and the relationship of mutation site to prognosis. And, they will take advantage of our new molecular and physiological insights into gene function to develop targeted therapies. can be fatal, and there is at present no treatment