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

纤毛是从大多数动物细胞表面突出的小的“触角状”结构。像天线一样，它们接收和处理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称为“纤毛病”的人类发育疾病。这些条件的范围从严重的，致命的条件，涉及复杂的缺陷，在多个器官，包括大脑，相对温和的和器官特异性的条件，如视网膜色素变性，这是一种形式的遗传性，进行性视力丧失。科学家们仍然没有完全理解纤毛是如何帮助控制大脑和视网膜发育的。虽然这些情况是个别罕见的，但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。这项研究提出要确定基因，单独或群体内（途径），形成纤毛的子结构称为过渡区。纤毛基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。许多导致纤毛病变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”）。我们处于独特的位置来做这项工作，研究人员团队在这一领域有着成功的记录：我们与该领域的其他工作人员建立了良好的研究伙伴关系，参与基因鉴定研究;我们拥有适当的最先进的技术，图像分析工具和经验;我们已经从现有的工作中产生并验证了大型数据集，我们现在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（“筛选命中”）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）相结合。纤毛和过渡区“门”的结构和功能所需的新基因的鉴定和表征提供了许多主要好处。首先，人们对疾病过程和疾病基因的正常功能有了重要的、往往是意想不到的科学见解，这些见解可能导致新的治疗方法。其次，新的纤毛基因通常可以为纤毛病患者和家族提供准确的基因检测，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相关性，因为纤毛最近被证明可以控制代谢，这可能与神经退行性疾病和代谢紊乱如胰岛素抵抗有关。因此，更好地了解纤毛生物学可能为开发药物或新治疗方法提供机会，以防止更常见疾病的进展（例如，糖尿病肥胖症），存在于一些纤毛病患者中。最后，我们希望我们的工作将提供新的见解纤毛疾病蛋白如何安排相对于彼此的过渡区内，以及这种分子组织如何促进这个离散区域的纤毛门控功能。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，并有助于扩大我们的工作对研究相关问题的科学家的影响。

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.