Investigating craniofacial phenotypes, cellular function, and membrane biochemistry of ciliary proteins Rsg1 and the Fam92-Chibby-Dzip module

研究睫状蛋白 Rsg1 和 Fam92-Chibby-Dzip 模块的颅面表型、细胞功能和膜生物化学

• 批准号: 10755056
• 负责人: Neftali Vazquez
• 金额: $ 3.92万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10755056
• 关键词: 3-Dimensional; Affect; Alleles; Animal Model; Binding; Biochemical; Biochemistry; Biological Assay; Cell membrane; Cell physiology; Cells; Cellular biology; Cephalic; Cilia; Cilium Microtubule; Congenital Disorders; Data; Development; Disease; Docking; Dysmorphology; Embryo; Embryonic Development; Etiology; Face; Functional disorder; Gene Expression Profiling; Genes; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Hamartoma; Head; Homeostasis; Human; Image; In Vitro; Left; Letters; Link; Lipid Binding; Lipid Biochemistry; Lipids; Maps; Mediating; Membrane; Membrane Biology; Molecular; Morphology; Mutation; Neural Crest; Orofaciodigital Syndromes; Palate; Patients; Phenotype; Play; Proliferating; Proteins; Proteomics; Public Health; Research; Role; Structural defect; Structure; System; Testing; Tongue; Vesicle; Work; Xenopus; body system; ciliopathy; cilium biogenesis; craniofacial; craniofacial development; craniofacial disorder; craniofacial structure; genetic variant; in vitro Assay; in vivo; in vivo imaging; insight; kinetosome; knock-down; microCT; neuroregulation; protein complex; protein function; superresolution microscopy

Abstract: Craniofacial differences are among the most common congenital disorders in humans. There are many regulatory factors at play during development of the head and face, with much left to understand. The dysfunction of the ciliogenesis and planar polarity effectors (CPLANE) are a known cause of human Orofaciodigital Disorders (OFD). The Rsg1 subunit of CPLANE is essential for ciliary function, but it remains among the least-studied components, and its mechanisms of action remain largely unexplored. Importantly, my preliminary data suggest that Rsg1 interacts with Fam92, Chibby, and Dzip1, proteins required for basal body docking and transition zone assembly. In this proposed research, the craniofacial developmental differences after disruption of Rsg1 and Fam92 will be explored in a model animal, with a specific focus on neural crest development. In vivo live imaging of ciliated cells will be studied to determine the cellular function of these proteins. Lastly, the biochemical function of the Fam92 BAR domains and disordered regions for membrane morphology will be explored in in vitro systems. Thus, the whole embryo, cellular, and biochemical functions of ciliary proteins Rsg1 and the Fam92- Chibby-Dzip1 module will be elucidated by the proposed work, which in turn will advance our understanding of congenital craniofacial disorders.

抽象的： 颅面差异是人类最常见的先天性疾病之一。有许多 在头部和面部发育过程中发挥作用的调节因素，还有很多需要理解的地方。这 纤毛发生和平面极性效应器 (CPLANE) 的功能障碍是人类 口颌面数字疾病（OFD）。 CPLANE 的 Rsg1 亚基对于纤毛功能至关重要，但它仍然存在 是研究最少的成分之一，其作用机制在很大程度上仍未被探索。重要的是， 我的初步数据表明 Rsg1 与 Fam92、Chibby 和 Dzip1 相互作用，这些蛋白质是基础蛋白所需的 车身对接和过渡区组装。 在这项拟议的研究中，Rsg1 和 Fam92 破坏后的颅面发育差异将 在模型动物中进行探索，特别关注神经嵴发育。体内实时成像 将研究纤毛细胞以确定这些蛋白质的细胞功能。最后，生化功能 将在体外探索 Fam92 BAR 结构域和膜形态无序区域的结构 系统。因此，纤毛蛋白 Rsg1 和 Fam92- 的整个胚胎、细胞和生化功能 Chibby-Dzip1 模块将通过拟议的工作进行阐明，这反过来又将增进我们对 先天性颅面疾病。