Genetic and cellular basis of functional cilia assembly

功能性纤毛组装的遗传和细胞基础

• 批准号: MC_UU_00007/14
• 负责人: Pleasantine Mill
• 金额: $ 234.2万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Intramural
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MC_UU_00007%2F14
• 关键词: Genetic; cellular; basis; functional; cilia

Cilia are specialized structures found on the surface of most mammalian cells, playing key sensory and sometimes movement functions. Defects in cilia function result in a broad range of genetic diseases termed ciliopathies. These can have devastating effects on human development (birth defects) or postnatal health, including blindness, obesity and kidney failure. Hundreds of genes are involved in building and maintaining this highly conserved structure, which is highly dynamic and biochemically complex. However, we know very little about why some cilia types are more affected in human disease than others. In order to understand how different cell types have configured cilia as specialized signaling ‘antennae’ to interpret environmental signals, we have engineered a series of mice expressing the latest molecular tags and markers to allow us to exquisitely profile cilia subtypes, in both healthy and diseased states. Ciliopathies are rare genetic diseases, for which there are no effective treatments. For a subset of these diseases affecting accessible tissues, like the airways of primary ciliary dyskinesia (PCD) patients, we have been developing genome editing strategies to determine can we fix the right cells types efficiently and whether this is treatment well-tolerated. We hope to better understand the disease mechanisms underlying ciliopathies in order to develop effective diagnostic as well as therapeutic strategies to benefit patients and their families.

纤毛是大多数哺乳动物细胞表面的特殊结构，起着关键的感觉和运动功能。纤毛功能缺陷导致广泛的遗传性疾病，称为纤毛病。这些可能对人类发育（出生缺陷）或产后健康造成毁灭性影响，包括失明、肥胖和肾衰竭。数百个基因参与构建和维持这种高度保守的结构，它是高度动态和生物化学复杂的。然而，我们对为什么某些纤毛类型在人类疾病中比其他类型更容易受到影响知之甚少。为了了解不同的细胞类型如何配置纤毛作为专门的信号“天线”来解释环境信号，我们设计了一系列表达最新分子标签和标记的小鼠，使我们能够在健康和患病状态下精确地描绘纤毛亚型。纤毛病是一种罕见的遗传病，目前尚无有效的治疗方法。对于影响可及组织的这些疾病的一部分，如原发性纤毛运动障碍（PCD）患者的气道，我们一直在开发基因组编辑策略，以确定我们能否有效地修复正确的细胞类型，以及这种治疗是否耐受性良好。我们希望更好地了解纤毛病的发病机制，以便制定有效的诊断和治疗策略，使患者及其家属受益。

项目成果

Proceedings of the 4th BEAT-PCD Conference and 5th PCD Training School.

• DOI: 10.1186/s12919-020-00191-3
• 发表时间: 2020-01-01
• 期刊: BMC proceedings
• 作者: Gardner, Laura E;Horton, Katie L;Hogg, Claire
• 通讯作者: Hogg, Claire

Primary cilia as dynamic and diverse signalling hubs in development and disease.

• DOI: 10.1038/s41576-023-00587-9
• 发表时间: 2023-07
• 期刊: Nature reviews. Genetics
• 作者: Mill P;Christensen ST;Pedersen LB
• 通讯作者: Pedersen LB

ZMYND10 functions in a chaperone relay during axonemal dynein assembly.

• DOI: 10.7554/elife.34389
• 发表时间: 2018-06-19
• 期刊: eLife
• 影响因子: 7.7
• 作者: Mali GR;Yeyati PL;Mizuno S;Dodd DO;Tennant PA;Keighren MA;Zur Lage P;Shoemark A;Garcia-Munoz A;Shimada A;Takeda H;Edlich F;Takahashi S;von Kreigsheim A;Jarman AP;Mill P
• 通讯作者: Mill P

A Cell/Cilia Cycle Biosensor for Single-Cell Kinetics Reveals Persistence of Cilia after G1/S Transition Is a General Property in Cells and Mice.

• DOI: 10.1016/j.devcel.2018.10.027
• 发表时间: 2018-11-19
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Ford MJ;Yeyati PL;Mali GR;Keighren MA;Waddell SH;Mjoseng HK;Douglas AT;Hall EA;Sakaue-Sawano A;Miyawaki A;Meehan RR;Boulter L;Jackson IJ;Mill P;Mort RL
• 通讯作者: Mort RL

TUBB4B variants specifically impact ciliary function, causing a ciliopathic spectrum

TUBB4B 变异特别影响纤毛功能，导致纤毛病谱

• DOI: 10.1101/2022.10.19.22280748
• 发表时间: 2022
• 作者: Mechaussier S