Interrogation of Neurological Pathologies Associated with Mutations in Kif1a

项目摘要 KAND（KIF 1A相关神经系统疾病）是由KIF 1A基因突变引起的，KIF 1A基因是一种微管， 在神经元中负责运输细胞货物的依赖性运动蛋白。大多数突变 是显性错义突变，聚集在蛋白质的保守马达结构域，并导致 从儿童开始的一系列神经学表型，包括肌无力，小头畸形， 周围神经病变、智力残疾、自闭症、视神经和小脑萎缩。如果不治疗， 受KAND影响的儿童和成人遭受他们的活动性、视力甚至早期视力的逐渐丧失。 死于顽固性癫痫和呼吸系统疾病并发症。小鼠模型是一个重要的组成部分 既了解疾病机制，又作为临床前试验的关键平台， 治疗学不幸的是，小鼠模型，以促进我们对KAND生物学和治疗的理解， 严重缺乏，尽管很容易达到。 这项建议旨在建立在我们目前的知识KAND设计小鼠模型，不仅提供 KAND疾病病理生理学的患者化身，但也将有助于解决围绕 治疗补救的时机、过表达的影响、有效治疗所需的细胞类型以及 疾病调节需要多少遗传校正。重要的是，这些模型将是有价值的前- 治疗的临床试验。这项提案中描述的工作利用了最近出版的《自然史》 我们的临床合作者Wendy Chung博士的研究提供了对临床特征的持续洞察， 与该患者群体相关的患病率和生物标志物。我们的总体目标是提供科学 社区拥有精心设计、经过严格测试的小鼠模型，重现了KAND疾病的关键方面 在整个学术界和工业界用于研究和治疗的表现，不受限制， 的发现

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.