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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：
10328907
负责人：
Wendy K Chung
金额：
$ 64.13万
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/10328907
关键词：
Adult Affect Age Agonist Animal Model Atrophic Axonal Transport Behavior Behavioral Binding Biological Assay Biomechanics Biophysics Blood - brain barrier anatomy 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 Play 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 base clinical diagnosis clinical phenotype cognitive function college falls gain of function gene function genetic testing human disease in vivo individual patient information gathering insight medical schools migration mimetics mouse model mutant mutant mouse model nervous system development nervous system disorder neurodevelopment neuron development 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

人类驱动蛋白基因 KIF1A 的突变会导致多种神经系统缺陷。这种综合症有由于这种情况的罕见性，其定义仍然不明确。这个提案汇集了非常不同的，但哥伦比亚大学医学院的 Wendy Chung 博士的专业知识具有高度互补性，她是人类遗传病；同样来自哥伦比亚大学的 Richard Vallee 博士是 Kif1a 在神经元中作用的专家发育和生理学；阿尔伯特·爱因斯坦医学院的 Arne Gennerich 博士是该领域的专家运动蛋白生物物理学。 Chung 博士的实验室开发了临床和计算方法来编译来自当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她的实验室将这种情况称为“KAND KIF1A 相关神经系统疾病”。这是一组异质性的严重神经退行性疾病，包括痉挛性截瘫、周围神经退行性疾病神经病变、视神经萎缩、大脑和小脑萎缩、认知障碍和癫痫发作。这条件可用。该项目的总体目标是获得足够的临床信息以了解 KAND 的全部症状；确定如何 Kif1a 运动域内不同位点的突变影响临床结果；了解细胞和该综合征的发育原因；并确定小分子试剂来治疗它。目标 1 将是根据快速增长的患者数据库定义 KAND 的自然史并将临床相关联 KIF1A 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来确定分子和细胞后果 Kif1a 突变。 Aim3将使用Kif1a突变小鼠来确定纵向和横向条件对模型生物体的影响，并更全面地测试 BDNF 在 KAND 和小分子 BDNF 模拟物作为 KAND 治疗剂的价值。这些研究非常重要由于多种原因。它们将极大地扩展我们识别和表征稀有物质的能力疾病。他们将提供对运动蛋白相关疾病的分子基础的详细见解。他们将提供有关疾病进展和突变关系的广泛新信息部位进行预测。而且，他们将利用我们对基因的新分子和生理学见解开发靶向治疗的功能。可能致命，目前尚无治疗方法