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

• 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

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.

纤毛是从大多数动物细胞表面伸出的小的“触角状”结构。就像天线一样，它们接收和传递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。这在发育过程中尤其重要，纤毛缺陷会导致一系列人类发育疾病，称为“纤毛疾病”。这些疾病的范围从严重的致命疾病，涉及包括大脑在内的多个器官的复杂缺陷，到相对轻微和器官特有的疾病，如视网膜色素变性，这是一种遗传性进行性失明。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的发育。虽然这些情况个别罕见，但总体而言，它们是婴儿和幼儿发病和死亡的常见原因，但仍然很难诊断和治疗。这项研究建议识别单独或在群体(路径)内有助于纤毛亚结构形成的基因，称为过渡区。纤毛底部的过渡区被认为是一种‘门’，控制着哪些信号转导分子被允许进入和离开纤毛。许多导致纤毛疾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，我们将利用最近令人兴奋的基因技术进步，使我们能够评估每一个基因对纤毛和过渡区形成的贡献(“反向遗传学筛查”)。我们处于开展这项工作的得天独厚的位置，调查人员团队在这一领域有着公认的成功记录：我们与该领域的其他工作人员结成了出色的研究伙伴关系，参与基因鉴定研究；我们拥有适当的最先进技术、图像分析工具和经验；我们已经从现有工作中产生并验证了大量数据集，现在我们希望在本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。识别和表征纤毛和过渡区‘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进行了重要的、往往是意想不到的科学见解，这可能导致新的治疗方法。其次，新的纤毛基因通常能够对纤毛疾病患者和家庭进行准确的基因测试，从而改善诊断和遗传咨询。第三，我们提议的工作具有更广泛的生物学相关性，因为纤毛最近被证明控制新陈代谢，这可能与神经退行性疾病和代谢紊乱有关，如胰岛素抵抗。因此，更好地了解纤毛生物学可能为开发药物或新的治疗方法以防止更常见疾病(如糖尿病)的进展提供机会。肥胖)，出现在一些睫状病患者身上。最后，我们预计，我们的工作将为纤毛疾病蛋白在过渡区内如何相互排列，以及这种分子组织如何促进纤毛的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中其他地方存在的分子‘门’产生重要影响，并有助于将我们的工作的影响扩大到致力于相关问题的科学家。

项目成果

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

• DOI: 10.1101/2020.11.26.393801
• 发表时间: 2020
• 作者: Lake A

RNASeq Analysis of a Pax3-Expressing Myoblast Clone in-Vitro and Effect of Culture Surface Stiffness on Differentiation

体外表达 Pax3 的成肌细胞克隆的 RNASeq 分析以及培养物表面硬度对分化的影响

• DOI: 10.21203/rs.3.rs-871095/v1
• 发表时间: 2021
• 作者: Richardson L

Obituary: Jarema Malicki (1965-2019)

讣告：贾雷玛·马里奇（1965-2019）

• DOI: 10.1242/dev.176677
• 发表时间: 2019
• 期刊: Development
• 影响因子: 4.6
• 作者: Johnson C

Interpreting ciliopathy-associated missense variants of uncertain significance (VUS) in an animal model

解释动物模型中与纤毛病相关的意义不确定的错义变异 (VUS)

• DOI: 10.1101/2021.06.17.448799
• 发表时间: 2021
• 作者: Lange K