Bilateral BBSRC-SFI: Structure-function relationships in the ciliary transition zone

双边 BBSRC-SFI：睫状过渡区的结构-功能关系

基本信息

批准号：
BB/P007791/1
负责人：
Colin Johnson
金额：
$ 41.72万
依托单位：
University of Leeds
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FP007791%2F1
关键词：
Bilateral BBSRC SFI Structure function

项目摘要

Cilia are small 'antennae-like' structures which protrude from the surface of most animal cells. Like antennae, they receive and transduce signals from other cells and their surroundings in order to coordinate appropriate cell behaviours. This is especially important in development, and defects in cilia lead to a range of human developmental diseases called "ciliopathies". These conditions range from severe, lethal conditions that involve complex defects in multiple organs including the brain, to relatively mild and organ-specific conditions such as retinitis pigmentosa, which is a form of hereditary, progressive sight loss. Scientists still do not fully understand how cilia help to control brain and retina development. Although these conditions are individually rare, collectively they are a common cause of morbidity and mortality in babies and young children but remain difficult to diagnose and treat.This research proposes to identify genes that contribute individually, or within groups (pathways), to the formation of a sub-structure of the cilium called the transition zone. The transition zone at the base of the cilium is thought to function as a type of 'gate', controlling which signal transduction molecules are allowed to enter and exit the cilium. Many of the genes that cause ciliopathies are thought to function in the transition zone and regulate its 'gating' function. To achieve our aims, we will take advantage of recent exciting advances in genetic technology that allow us to evaluate the contribution of every gene to cilia and transition zone formation ("reverse genetics screen"). We are uniquely placed to do this work and the team of investigators have a proven track record of success in this field: we have formed excellent research partnerships with other workers in the field to participate in gene identification studies; we have the appropriate state-of-the-art technology, image analysis tools and experience; and we have already produced and validated large data-sets from existing work that we now wish to exploit more extensively in the present research proposal. We will study key genes ("screen hits") and their contributions to cilia and transition zone formation, and, in particular we will use specialised cell model systems in combination with a versatile animal model (a nematode roundworm).The identification and characterisation of new genes required for the structure and function of the cilium and the transition zone 'gate' provides a number of major benefits. Firstly, important and often unexpected scientific insights are made into disease processes and into the normal function of the disease gene that can lead to new treatments. Secondly, new ciliary genes often enable accurate genetic testing for patients and families with ciliopathies, which improve diagnosis and genetic counselling. Thirdly, our proposed work has a wider biological relevance because cilia have recently been shown to control metabolism, which may link to neurodegenerative diseases and metabolic disorders such as insulin resistance. Thus, a better understanding of cilium biology may provide opportunities for developing drugs or new treatments to prevent the progression of more common ailments (e.g., diabetes. obesity) that present in some ciliopathy patients. Finally, we expect that our work will provide new insights into how cilia disease proteins are arranged relative to one another within the transition zone, and how this molecular organisation facilitates the gating function of this discrete region of the cilium. This new knowledge will have important implications for molecular 'gates' that exist elsewhere in the cell, and serve to expand the impact of our work to scientists working on related questions.

纤毛是小的“触角状”结构，从大多数动物细胞的表面突出。像天线一样，它们接收和转换来自其他细胞及其周围环境的信号，以协调适当的细胞行为。这对于发育尤其重要，纤毛缺陷会导致一系列称为“纤毛病”的人类发育疾病。这些病症的范围从严重的致命病症（涉及包括大脑在内的多个器官的复杂缺陷）到相对轻微的器官特异性病症，例如色素性视网膜炎（一种遗传性进行性视力丧失）。科学家们仍然不完全了解纤毛如何帮助控制大脑和视网膜发育。尽管这些病症单独而言很少见，但总的来说，它们是婴儿和幼儿发病和死亡的常见原因，但仍然难以诊断和治疗。这项研究旨在识别单独或群体内（途径）促成形成的基因称为过渡区的纤毛子结构。纤毛底部的过渡区被认为起到一种“门”的作用，控制哪些信号转导分子可以进入和离开纤毛。许多引起纤毛病的基因被认为在过渡区发挥作用并调节其“门控”功能。为了实现我们的目标，我们将利用遗传技术的最新进展，使我们能够评估每个基因对纤毛和过渡区形成的贡献（“反向遗传学筛选”）。我们在开展这项工作方面处于得天独厚的优势，并且研究人员团队在该领域拥有良好的成功记录：我们与该领域的其他工作者建立了良好的研究伙伴关系，参与基因鉴定研究；我们拥有相应的最先进的技术、图像分析工具和经验；我们已经从现有工作中生成并验证了大型数据集，现在我们希望在当前的研究提案中更广泛地利用这些数据集。我们将研究关键基因（“屏幕点击”）及其对纤毛和过渡区形成的贡献，特别是我们将使用专门的细胞模型系统与多功能动物模型（线虫蛔虫）相结合。纤毛和过渡区“门”的结构和功能所需的新基因提供了许多主要好处。首先，对疾病过程和疾病基因的正常功能产生重要且常常意想不到的科学见解，从而可以带来新的治疗方法。其次，新的纤毛基因通常能够对患有纤毛病的患者和家庭进行准确的基因检测，从而改善诊断和遗传咨询。第三，我们提出的工作具有更广泛的生物学相关性，因为纤毛最近被证明可以控制新陈代谢，这可能与神经退行性疾病和胰岛素抵抗等代谢紊乱有关。因此，更好地了解纤毛生物学可能为开发药物或新疗法提供机会，以预防某些纤毛病患者中出现的更常见疾病（例如糖尿病、肥胖）的进展。最后，我们期望我们的工作将为纤毛疾病蛋白如何在过渡区内相对排列，以及这种分子组织如何促进纤毛这一离散区域的门控功能提供新的见解。这一新知识将对细胞其他地方存在的分子“门”产生重要影响，并有助于扩大我们的工作对研究相关问题的科学家的影响。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa.

DOI：
10.1038/s41467-018-06448-y
发表时间：
2018-10-12
期刊：
Nature communications
影响因子：
16.6
作者：
Buskin A;Zhu L;Chichagova V;Basu B;Mozaffari-Jovin S;Dolan D;Droop A;Collin J;Bronstein R;Mehrotra S;Farkas M;Hilgen G;White K;Pan KT;Treumann A;Hallam D;Bialas K;Chung G;Mellough C;Ding Y;Krasnogor N;Przyborski S;Zwolinski S;Al-Aama J;Alharthi S;Xu Y;Wheway G;Szymanska K;McKibbin M;Inglehearn CF;Elliott DJ;Lindsay S;Ali RR;Steel DH;Armstrong L;Sernagor E;Urlaub H;Pierce E;Lührmann R;Grellscheid SN;Johnson CA;Lako M
通讯作者：
Lako M

Drug and siRNA screens identify ROCK2 as a therapeutic target for ciliopathies

药物和 siRNA 筛选将 ROCK2 确定为纤毛病的治疗靶点