Functional genomics identification and characterization of novel disease genes, mechanisms and pathways of ciliogenesis

纤毛是从大多数动物细胞表面伸出的小结构，就像触角一样。就像天线一样，它们接收来自其他细胞及其周围环境的信号，并帮助细胞正常运作。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”。这些情况包括严重的致命疾病，包括大脑在内的多个器官的复杂缺陷，以及视网膜色素变性(RP)，这是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率和死亡率的常见原因，但仍然难以诊断和治疗。这项研究建议识别纤毛疾病中存在缺陷(“突变”)的基因，或单独或作为途径的一部分促成纤毛的形成。为了实现这一目标，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人类基因对纤毛形成的贡献(“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，调查团队在这一领域拥有被证明的成功记录：我们与家属、他们的临床医生和该领域的其他工作人员建立了出色的研究伙伴关系，以参与基因鉴定研究；我们拥有适当的最先进技术、图像分析工具和经验；我们已经从屏幕上产生并验证了非常庞大的数据集，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”)及其对纤毛形成的贡献，特别是我们将使用更紧密地模拟大脑和视网膜组织的特殊细胞系统。为了做到这一点，我们将使用小鼠和人类干细胞分化为神经元前体、神经元和视网膜细胞。重要的是，这种方法使我们能够研究视网膜病变患者视网膜组织中的纤毛。识别纤毛形成中的新基因提供了两个主要好处。首先，随着诊断和遗传咨询的改进，对患者和家属进行准确的基因检测成为可能。其次，对疾病机制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。特别是，我们从筛查中获得的初步证据表明，某些形式的RP可能是由视网膜中有缺陷的纤毛形成引起的，其发病机制此前尚不清楚。更好地了解这些过程可能会为开发药物或新的治疗方法提供机会，以防止常见形式的视网膜退化的疾病进展。我们还期待对其他常见疾病的原因有新的见解，如多囊肾病、脊柱裂和先天性心脏缺陷。

Cilia are small structures which protrude from the surface of most animal cells like antennae. Like antennae, they receive signals from other cells and their surroundings, and help the cell behave appropriately. 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 retinitis pigmentosa (RP) 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 are either defective ("mutated") in ciliopathies, or otherwise contribute to the formation of a cilium either individually or as part of a pathway. To achieve this aim, we will take advantage of recent exciting advances in genetic technology that allow us to evaluate the contribution of every human gene to cilia 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 families, their clinicians and 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 the very large data-set from the screen 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 formation, and, in particular we will use special cell systems that more closely model brain and retinal tissue. To do this, we will use both mouse and human stem cells differentiated into neuronal precursors, neurons and retinal cells. Importantly, this approach allows us to study cilia in retinal tissue derived from patients with RP.The identification of new genes in cilia formation provides two major benefits. Firstly, accurate genetic testing then becomes possible for patients and families, with improvements in diagnosis and genetic counselling. Secondly, important and often unexpected scientific insights are made into disease mechanisms and into the normal function of the disease gene that can lead to new treatments. In particular, we have preliminary evidence from the screen that certain forms of RP, for which the disease mechanism has been unclear previously, may be caused by defective cilia formation in the retina. A better understanding of these processes may provide opportunities for developing drugs or new treatments to prevent disease progression in common forms of retinal degeneration. We also expect new insights into the causes of other common conditions such as polycystic kidney disease, spina bifida and congenital heart defects.