Role of the Kinesin KIF1A in Neurological Disease

驱动蛋白 KIF1A 在神经系统疾病中的作用

基本信息

批准号：
10543786
负责人：
Wendy K Chung
金额：
$ 62.95万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-15 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10543786
关键词：
Adult Affect Age Agonist Atrophic Axonal Transport Behavior Behavioral Binding Biological Assay Biomechanics Biophysics Brain Brain-Derived Neurotrophic Factor Cerebral Palsy Cerebrum Child Clinical Clinical Data Computing Methodologies Databases Defect Development Diagnosis Dimerization Disease Disease Progression Embryonic Development Epilepsy Functional disorder Genes Genetic Diseases Genotype Goals Hereditary Spastic Paraplegia Human Human Genetics Impaired cognition Individual Inherited Intellectual functioning disability Intervention Kinesin Leg Mediating Medical Genetics Medicine Microtubules Modeling Molecular Motor Mus Mutant Strains Mice Mutation N-terminal Natural History Nerve Degeneration Nerve Growth Factor Receptors Neurodegenerative Disorders Neurodevelopmental Disorder Neurologic Neurons Nuclear Optic Nerve Outcome Pathogenesis Pathogenicity Patients Peripheral Nervous System Diseases Pharmaceutical Preparations Phenotype Physiological Physiology Prognosis Property Proteins Quality of life Rare Diseases Rattus Reagent Recombinants Rodent Model Role Seizures Severities Site Spastic Paraplegia Specialist Structure Symptoms Syndrome Testing Therapeutic Agents Therapeutic Intervention United States Universities Vision associated symptom autosome blood-brain barrier crossing clinical diagnosis clinical phenotype cognitive function college dominant genetic mutation falls gain of function gene function genetic testing human disease in vivo individual patient information gathering insight medical schools migration mimetics model organism mouse model mutant mutant mouse model nervous system development nervous system disorder neurodevelopment neuron development neuropathology neurotrophic factor novel novel therapeutic intervention novel therapeutics polypeptide rare condition single molecule small molecule targeted treatment therapeutic candidate therapeutically effective tool vesicle transport

项目摘要

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

人驱动蛋白基因KIF1A中的突变会导致多种神经缺陷。该综合征具有由于病情的稀有性，定义很差。该提议汇集了截然不同的但是，哥伦比亚大学医学院温迪·钟博士的高度互补专业知识，专家人遗传疾病；理查德·瓦利（Richard Vallee）博士也在哥伦比亚（Columbia），是KIF1A在神经元中角色的专家发展和生理；以及阿尔伯特·爱因斯坦医学院的Arne Gennerich博士，专家运动蛋白生物物理学。 Chung博士实验室开发了临床和计算方法来编译来自本地和全球范围内，严重程度和各种症状的患者的信息在这种情况下，她的实验室称其为KAND KIF1A相关的神经系统疾病。这是一组严重的神经退行性疾病，包括痉挛性截瘫，周围神经病，视神经萎缩，大脑和小脑萎缩，认知障碍和癫痫发作。这可用条件。该项目的所有目标是获得足够的临床信息，以了解智能症状的全范围；确定如何 KIF1A运动结构域内不同部位的突变影响临床结果；了解细胞和综合征的发展原因；并鉴定小分子试剂以对其进行处理。目标1将是根据迅速增加的患者数据库来定义KAND的自然历史并将临床相关 KIF1A基因型的严重程度和进展速率。 AIM 2将是使用高级单分子生物物理和体内轴突转运方法，以确定分子和细胞的后果 KIF1A突变。 AIM3将使用KIF1A突变小鼠确定纵向和横截面模型生物体中该疾病的影响，并更彻底地测试BDNF在kand和kand中的作用小分子bdnf mimetics作为kand治疗剂的值。这些研究非常重要出于多种原因。他们将极大地扩展我们识别和表征稀有的能力疾病。他们将提供有关运动蛋白相关疾病的分子基础的详细见解。他们将提供有关疾病进展和突变关系的广泛新信息预后的位置。而且，他们将利用我们对基因的新分子和生理见解开发目标疗法的功能。可能是致命的，目前没有治疗