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.

项目概要 纤毛在人类发育和健康中发挥着重要作用，体现了纤毛的普遍性和多样性。 在由纤毛缺陷引起的多症状纤毛病中，纤毛病基因突变的临床严重程度各不相同。 细胞类型之间的差异，包括囊性肾病、神经和骨骼缺陷、视网膜变性、 而相同的基本鞭毛内运输（IFT）机制构建了所有这些。 对于纤毛和鞭毛，我们对纤毛特化的机制知之甚少，例如纤毛。 产生细胞外囊泡 (EV)。 EV 脱落是纤毛的一般特性还是特殊特性。 某些纤毛类型的特征尚不清楚，纤毛 EV 的功能及其对纤毛病的贡献尚不清楚。 该项目的长期目标是确定调节纤毛的分子机制。 线虫内唇型的特化、重塑、可塑性、EV 生物发生和纤毛功能。 2 (IL2) 神经元表现出多种特化：它们具有独特的微管超微结构、专门的 IFT、 IL2 纤毛过渡区 (TZ) 和轴丝在结构上是可塑的，并且是从一个区域改造而来的。 动物发育过程中结构的变化：从规范的 9+0 结构到非规范的 6+0 结构。 纤毛和鞭毛具有 9 倍微管双峰对称性，观察到微管数量的变化 在自然界中，肾初级纤毛不符合 9+0 范式。 一些纤毛缺陷（纤毛病）可能会在以后得到纠正，我们的假设得到了最近的支持。 发现常染色体显性多囊肾病是可逆的，并且肾脏表现出 我们简单的线虫模型使我们能够揭示调节纤毛的机制。 我们发现 TZ 重塑需要 IFT 和微管蛋白代码 - 组合使用。 微管蛋白同种型、谷氨酰化和微管相关蛋白。 (NPHP-RC) 与 TZ 相关蛋白的缺陷有关，包括肾结核、 Meckel Gruber (MKS)、Joubert (JBTS) 和 Senior-Løken 综合征的功能丧失的临床严重程度。 NPHP-RC 基因因细胞和纤毛类型而异，因此有必要了解纤毛和 EV 生物学 我们将使用线虫来识别驱动过渡区和轴丝的机制。 非典型初级纤毛的重塑和可塑性是保守的，但人们知之甚少。 关于纤毛如何以及为何产生电动汽车，我们将测试纤毛重塑和非规范的假设。 结构影响 EV 生物发生和 EV 功能。