Interrogation of Neurological Pathologies Associated with Mutations in Kif1a

与 Kif1a 突变相关的神经病理学研究

基本信息

批准号：
10728701
负责人：
Cathleen M Lutz
金额：
$ 44.2万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10728701
关键词：
Academia Address Adult Affect Alleles Atrophic Axonal Transport Biological Markers Biology Cells Cessation of life Child Childhood Childhood Neurological Disorder Clinical Communities DNA Data Defect Development Developmental Delay Disorders Disease Functional disorder Genes Genetic Genetic Engineering Goals Heterozygote Histology Human Industry Intellectual functioning disability Intractable Epilepsy Investigation Kinesin Knowledge Microcephaly Microtubules Missense Mutation Modeling Motor Mus Muscle Weakness Muscle hypotonia Mutant Strains Mice Mutation Natural History Nervous System Neurologic Neurons Optic Nerve Patients Peripheral Nervous System Diseases Phase Phenotype Preclinical Testing Prevalence Probability Proteins Publishing Reproducibility Research Resources Route Seizures Tertiary Protein Structure Testing Therapeutic Therapeutic Intervention Time Transgenic Mice Validation Vision Visual impairment Work autism spectrum disorder base editor cell type design dimer disease diagnosis disease phenotype dominant genetic mutation effective therapy efficacy evaluation experimental study gene replacement genotyped patients improved induced pluripotent stem cell insight mortality mouse model mutation correction nervous system disorder neurological pathology novel therapeutics overexpression prime editing prime editor protein function respiratory therapeutic evaluation

Academia Address Adult Affect Alleles Atrophic Axonal Transport Biological Markers Biology Cells Cessation of life Child Childhood Childhood Neurological Disorder Clinical Communities DNA Data Defect Development Developmental Delay Disorders Disease Functional disorder Genes Genetic Genetic Engineering Goals Heterozygote Histology Human Industry Intellectual functioning disability Intractable Epilepsy Investigation Kinesin Knowledge Microcephaly Microtubules Missense Mutation Modeling Motor Mus Muscle Weakness Muscle hypotonia Mutant Strains Mice Mutation Natural History Nervous System Neurologic Neurons Optic Nerve Patients Peripheral Nervous System Diseases Phase Phenotype Preclinical Testing Prevalence Probability Proteins Publishing Reproducibility Research Resources Route Seizures Tertiary Protein Structure Testing Therapeutic Therapeutic Intervention Time Transgenic Mice Validation Vision Visual impairment Work autism spectrum disorder base editor cell type design dimer disease diagnosis disease phenotype dominant genetic mutation effective therapy efficacy evaluation experimental study gene replacement genotyped patients improved induced pluripotent stem cell insight mortality mouse model mutation correction nervous system disorder neurological pathology novel therapeutics overexpression prime editing prime editor protein function respiratory therapeutic evaluation

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项目摘要

PROJECT SUMMARY KAND (KIF1A-associated neurological disorder) is caused by mutations in the KIF1A gene - a microtubule- dependent motor protein that is responsible to transport cellular cargos in neurons. The majority of mutations are dominant missense mutations that cluster in the conserved motor domain of the protein and lead to a spectrum of neurological phenotypes beginning in childhood, including muscle weakness, microcephaly, peripheral neuropathy, intellectual disability, autism, optic nerve and cerebellar atrophy. Without treatment, children and adults affected by KAND suffer from the progressive loss of their mobility, vision and even early death due to intractable epilepsy and complications of respiratory illness. Mouse models are a critical component to both understanding disease mechanisms and to serve as a key platform for preclinical testing of novel therapeutics. Unfortunately, mouse models to advance our understanding of KAND biology and therapeutics are severely lacking, although very much in reach. This proposal aims to build on our current knowledge of KAND to design mouse models that will not only provide patient avatars for KAND disease pathophysiology but will also serve to address important questions around the timing of therapeutic rescue, effects of overexpression, what cell types are required for effective treatment and how much genetic correction is required for disease modulation. Importantly, the models will be valuable for pre- clinical testing of therapeutics. The work described in this proposal leverages recently published Natural History Studies by our clinical collaborator, Dr. Wendy Chung, which provides ongoing insight into the clinical features, prevalence and biomarkers associated with this patient community. Our overall goals are to provide the scientific community with well designed, rigorously tested mouse models that recapitulate key aspects of KAND disease manifestations to be used, without restriction, throughout academia and industry for research and therapeutic discovery.

项目摘要 KAND（KIF1A相关神经系统疾病）是由KIF1A基因突变引起的 - 微管负责转运神经元中细胞肉类的依赖运动蛋白。大多数突变是主要的错义突变，这些突变聚集在蛋白质的保守运动结构域中，并导致从童年开始的神经表型的光谱，包括肌肉无力，小头畸形，周围神经病，智力障碍，自闭症，视神经和小脑萎缩。没有治疗，受kand影响的儿童和成人遭受了其流动性，视力甚至早期的逐渐丧失死亡是由于顽固性癫痫和呼吸道疾病并发症而导致的。鼠标模型是关键组件了解疾病机制，并作为新型临床前测试的关键平台疗法。不幸的是，鼠标模型可以提高我们对智能生物学和治疗剂的理解严重缺乏，尽管触及很大。该建议旨在基于我们当前对KAND的知识来设计鼠标模型，不仅可以提供患者智能病理生理学的患者化身，但也将有助于解决有关的重要问题治疗救援的时间，过表达的影响，有效治疗需要哪种细胞类型和疾病调节需要多少遗传纠正。重要的是，这些模型对于预审查很有价值治疗疗法的临床测试。该提案利用中描述的工作最近发表了自然历史我们的临床合作者Wendy Chung博士的研究，该博士提供了持续了解临床特征的洞察力与该患者社区相关的患病率和生物标志物。我们的总体目标是提供科学具有精心设计，严格测试的鼠标模型的社区，概括了Kand病的关键方面在整个学术界和行业中，都需要使用的表现形式进行研究和治疗发现。