Nephronophthisis-related ciliopathies and ciliary specialization

肾结核相关纤毛病和纤毛特化

• 批准号: 10585692
• 负责人: MAUREEN M BARR
• 金额: $ 59.22万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585692
• 关键词: Adult; Animals; Automobile Driving; Autosomal Dominant Polycystic Kidney; Basic Science; Biogenesis; Biological Models; Biology; Caenorhabditis elegans; Cardiac; Cells; Centrosome; Cilia; Clinical; Code; Cystic Kidney Diseases; Defect; Development; Disease; Event; Flagella; Future; Gatekeeping; Gene Expression Profiling; Gene Mutation; Genes; Goals; Health; Homologous Gene; Human; Human Development; Human body; Image; Interphase Cell; Kidney; Leber' s amaurosis; Length; Male Infertility; Measures; Microtubule-Associated Proteins; Microtubules; Modeling; Molecular; Mutation; Nature; Nephronophthisis; Neurologic; Neurons; Play; Property; Proteins; Proteomics; Regulation; Resolution; Retina; Retinal Degeneration; Role; Severities; Situs Inversus; Sorting; Spatial Distribution; Structure; Symptoms; Syndrome; System; Tertiary Protein Structure; Testing; Therapeutic; Tissues; Tubulin; Variant; Visualization; cell type; ciliopathy; combinatorial; developmental plasticity; electron tomography; extracellular vesicles; gene therapy; human disease; in vivo; innovation; katanin; loss of function; mutant; nephronophthisis-related ciliopathy; proteostasis; regeneration potential; skeletal; success; vesicular release

Project Summary Cilia play essential roles in human development and health. Ciliary ubiquity and diversity are reflected in multi-symptom ciliopathies caused by ciliary defects. The clinical severity of ciliopathy gene mutations varies between cell types and includes cystic kidney disease, neurological and skeletal defects, retinal degeneration, situs inversus, and male infertility. While the same basic intraflagellar transport (IFT) machinery constructs all cilia and flagella, the mechanisms underlying ciliary specialization are poorly understood. For example, cilia produce extracellular vesicles (EVs). Whether EV shedding is a general property of cilia or a specialized feature of some cilia types is unknown. The functions of ciliary EVs and their contributions to ciliopathies are also poorly understood. The long-term goal of this project is to identify molecular mechanisms regulating ciliary specialization, remodeling, plasticity, EV biogenesis, and EV functions. Cilia of the C. elegans inner labial-type 2 (IL2) neurons display several specializations: they have unique microtubule ultrastructure, specialized IFT, and shed EVs. The IL2 ciliary transition zone (TZ) and axoneme is structurally plastic and remodels from one structure to another during animal development: from a canonical 9+0 to non-canonical 6+0 structure. While cilia and flagella share a 9-fold microtubule doublet symmetry, variations in microtubule numbers are observed in nature. Renal primary cilia do not conform to the 9 + 0 paradigm. This developmental plasticity suggests that some ciliary defects (ciliopathies) may be corrected at later times. Our hypothesis is supported by the recent discovery that autosomal dominant polycystic kidney disease is reversible, and that the kidney displays structural plasticity. Our simple C. elegans model allows us to uncover mechanisms that regulate ciliary remodeling and plasticity. We found that TZ remodeling requires IFT and the tubulin code – combinatorial use of tubulin isotypes, glutamylation, and microtubule-associated proteins. Nephronophthisis-related ciliopathies (NPHP-RCs) are associated with defects in TZ-associated proteins. NPHP-RCs include nephronophthisis, Meckel Gruber (MKS), Joubert (JBTS), and Senior-Løken syndromes. The clinical severity of loss of function of NPHP-RC genes varies between cell and cilia types, thus it is imperative to understand ciliary and EV biology in a variety of contexts. We will use C. elegans to identify mechanisms driving transition zone and axonemal remodeling and plasticity in non-canonical primary cilia. Ciliary EV shedding is a conserved, yet little is known about how and why cilia make EVs. We will test the hypotheses that ciliary remodeling and a non-canonical structure impacts EV biogenesis and EV function.

项目摘要 纤毛在人类发展和健康中扮演重要角色。纤毛的普及和多样性反映了 在由纤毛缺陷引起的多症纤毛病中。纤毛病基因突变的临床严重程度各种 在细胞类型之间，包括囊性肾脏疾病，神经系统和骨骼缺陷，残留变性， 现场逆向和男性不育症。虽然相同的基本flagellar运输（IFT）机械构建了所有 纤毛和鞭毛，纤毛专业化的机制知之甚少。例如，纤毛 产生细胞外蔬菜（EV）。 Ev脱落是纤毛的一般财产还是专业的 某些纤毛类型的特征尚不清楚。纤毛电动汽车的功能及其对纤毛病的贡献是 也很懂事。该项目的长期目标是鉴定用于治疗睫状的分子机制 专业化，重塑，可塑性，EV生物发生和EV功能。秀丽隐杆线虫内唇型的纤毛类型 2（IL2）神经元显示了几种专业：它们具有独特的微管超微结构，专门的IFT， 和电动汽车。 IL2睫状过渡区（TZ）和轴突是结构上的塑料，并重塑了一个 动物发育过程中另一个结构：从规范的9+0到非典型的6+0结构。尽管 纤毛和鞭毛共享9倍的微管双线对称性，观察到微管数的变化 本质。肾纤毛不符合9 + 0范式。这种发展可塑性表明 以后可以纠正一些睫状缺陷（纤毛病）。我们的假设得到了最近的支持 发现常染色体显性多囊性肾脏疾病是可逆的，肾脏显示 结构可塑性。我们简单的秀丽隐杆线虫模型使我们能够发现调节睫状的机制 重塑和可塑性。我们发现TZ重塑需要IFT和微管蛋白代码 - 组合使用 小管蛋白同种型，谷氨酸和微管相关蛋白。肾植物相关的纤毛病 （NPHP-RC）与TZ相关蛋白中的缺陷有关。 NPHP-RCS包括肾植物， Meckel Gruber（MKS），Joubert（JBTS）和Senior-Løken综合征。功能丧失功能的临床严重程度 NPHP-RC基因在细胞和纤毛类型之间有所不同，因此必须了解睫状生物和EV生物学 在各种情况下。我们将使用秀丽隐杆线虫来识别驱动过渡区和轴突的机制 非经典原发性纤毛的重塑和可塑性。睫状电动式脱落是一个构成的，但鲜为人知 关于纤毛如何以及为什么制作电动汽车。我们将测试睫状重塑和非典型的假设 结构影响EV生物发生和EV功能。