Role of the Kinesin KIF1A in Neurological Disease

人类激动素基因KIF1a的突变会导致各种神经缺陷。这种综合征有 由于这种疾病的罕见，仍然没有明确的定义。这项提议汇集了非常不同的、 但哥伦比亚大学医学院的温迪·钟博士的专业知识具有很强的互补性 人类遗传病；理查德·瓦莱博士，也是哥伦比亚大学的专家，研究Kif1a在神经元中的作用 阿尔伯特·爱因斯坦医学院的阿恩·根纳里奇博士是 运动蛋白质生物物理学。钟博士的实验室已经开发出临床和计算方法来汇编 来自本地和世界各地患者的有关相关症状的范围、严重程度和种类的信息 患有这种情况，她的实验室将其称为Kand KIF1A相关神经疾病。这是一组不同类型的严重神经退行性疾病，包括痉挛性截瘫、外周 神经病、视神经萎缩、脑和小脑萎缩、认知障碍和癫痫。这个 条件可用。这个项目的总体目标是 获得足够的临床信息，以了解Kand的所有症状；确定如何 Kif1a运动域中不同位置的突变会影响临床结果；为了了解细胞和 该综合征的发育原因；并寻找治疗该综合征的小分子试剂。目标1将是 根据快速增长的患者数据库和相关临床数据定义Kand的自然病史 KIF1A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确定阿司匹林的分子和细胞后果 Kif1a基因突变。Aim3将利用Kif1a突变小鼠来确定纵向和横截面 在模型生物体中条件的影响，并更全面地测试BDNF在KAND和 小分子脑源性神经营养因子模拟物作为Kand治疗剂的价值。这些研究具有重要的意义。 原因有很多。它们将极大地扩展我们识别和描述稀有物种的能力 疾病。他们将提供对运动蛋白相关疾病的分子基础的详细见解。 他们将提供关于疾病进展和突变关系的广泛新信息。 从部位到预后。而且，他们将利用我们对基因的新的分子和生理洞察 开发靶向治疗的功能。 可能是致命的，目前还没有治疗方法

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