Therapeutic rescue of an olfactory ciliopathy

嗅觉纤毛病的治疗性挽救

• 批准号: 8387360
• 负责人: Jeremy McIntyre
• 金额: $ 5.22万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8387360
• 关键词: Address; Adenoviruses; Affect; Afferent Neurons; Age; Anosmia; Bardet-Biedl Syndrome; Carrier Proteins; Cell physiology; Chronic Sinusitis; Cilia; Cystic kidney; Data; Defect; Deletion Mutation; Development; Disease; Etiology; Exhibits; Flagella; Functional disorder; Gene Delivery; Gene Expression; Genes; Goals; Hepatic Cyst; Hereditary Disease; Homeostasis; Human; Human Genetics; Hydrocephalus; Imaging Techniques; Immunohistochemistry; Individual; Injury; Knock-out; Knowledge; Leber' s amaurosis; Length; Maintenance; Methods; Modeling; Molecular Genetics; Molecular Motors; Mus; Mutagenesis; Mutant Strains Mice; Mutate; Mutation; National Research Service Awards; Olfactory Epithelium; Olfactory Mucosa; Organelles; Patients; Phenotype; Play; Point Mutation; Polycystic Kidney Diseases; Population; Process; Protein Biosynthesis; Proteins; Recovery of Function; Research; Research Training; Role; Series; Signaling Protein; Smell Perception; Stimulus; Symptoms; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; Training; adenoviral-mediated; body system; cell type; ciliopathy; cilium biogenesis; fluorescence imaging; improved; insight; mouse model; particle; photoreceptor degeneration; protein complex; protein transport; research study; restoration; therapy development

DESCRIPTION (provided by applicant): The proposed postdoctoral NRSA incorporates a comprehensive research and training plan for the study of protein trafficking and cilia function in the olfactory system. Cilia are evolutionarily conserved organelles that play important roles in both sensing external stimuli and maintaining cellular homeostasis. Ciliopathies are an emerging class of human genetic disorders in which cilia function is disrupted leading to a wide variety of tissue defects. Ciliopathies in human patients can be caused by point mutations or entire deletions of cilia related genes. One of the systems that are affected by these ciliopathies is the olfactory system, leading to a reduction or loss in the ability to smell. Individual olfactory sensory neurons (OSNs) contain over 20 cilia that project into the olfactory mucosa and are responsible for detecting odorants. Since olfactory cilia lack protein synthesis components, olfactory signaling proteins must be correctly targeted to and moved throughout the cilia by specific mechanisms. It is well established that proteins move throughout cilia by the process of Intraflagellar Transport (IFT). The role of IFT in olfactory cilia development, maintenance and function is largely unknown. Aim 1 of this proposal will use a mutant mouse strain, ORPK, in which cilia maintenance and function is altered. ORPK mice are unable to detect odorants as the olfactory cilia are largely absent. Using adenovirus, I will deliver a function copy of the mutated gene, IFT88, to OSNs in order to restore olfactory cilia and importantly olfactory function. Additionally this aim will concentrate on ways to improve gene delivery to OSNs, including the use of non-viral methods. Aim 2 will investigate cilia development and olfactory function in an olfactory specific IFT88 knockout. Both mutations and deletions underlie ciliopathies; however there may be differences in the phenotypes caused by these changes. In aim 2 I will investigate changes in olfactory ciliogenesis in the olfactory specific knockout as well as testing olfactory function. Finally I will test whether adenoviral gene delivery methods can restore defects caused by IFT88 deletion. The results from these studies will provide new insight into the roles of IFT in olfactory cilia development and maintenance. Importantly the results from this project will help in the development of therapies for patients with olfactory ciliopathies, and potential therapies for other types of olfactory dysfunction as well other organ systems affected by ciliopathies.

描述（由申请人提供）：拟议的博士后NRSA纳入了嗅觉系统中蛋白质运输和纤毛功能研究的全面研究和培训计划。纤毛是进化保守的细胞器，在感应外部刺激和维持细胞稳态中起着重要作用。纤毛病是一种新兴的人类遗传疾病，其中纤毛功能受到破坏，导致多种组织缺陷。人类患者的纤毛病可能是由点突变或纤毛相关基因缺失引起的。受这些纤毛病影响的系统之一是嗅觉系统，导致气味能力降低或损失。单个嗅觉的感觉神经元（OSN）包含20多个纤毛，这些纤毛将投射到嗅觉粘膜中，并负责检测气味剂。由于嗅觉纤毛缺乏蛋白质合成成分，因此必须通过特定机制正确靶向并在整个纤毛中移动嗅觉信号蛋白。众所周知，蛋白质通过flagellar内运输（IFT）的过程在整个纤毛中移动。 IFT在嗅觉纤毛，维护和功能中的作用在很大程度上是未知的。该提案的目标1将使用突变的小鼠应变，ORPK，其中纤毛维持和功能被改变。 ORPK小鼠无法检测出气味剂，因为嗅觉纤毛基本上不存在。使用腺病毒，我将将突变基因IFT88的功能副本传递到OSN，以恢复嗅觉纤毛，重要的是嗅觉函数。此外，此目标将集中在改善基因输送到OSN的方法上，包括使用非病毒方法。 AIM 2将在嗅觉特异性IFT88敲除中研究纤毛的发展和嗅觉功能。突变和缺失是纤毛病的基础；但是，这些变化引起的表型可能存在差异。在AIM 2中，我将研究嗅觉特异性敲除和测试嗅觉功能中嗅觉纤毛发生的变化。最后，我将测试腺病毒基因输送方法是否可以恢复由IFT88缺失引起的缺陷。这些研究的结果将为IFT在嗅觉纤毛开发和维护中的作用提供新的见解。重要的是，该项目的结果将有助于开发嗅觉纤维病患者的疗法，以及其他类型的嗅觉功能障碍的潜在疗法以及受纤毛病影响的其他器官系统。