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突出的小结构，如触角。像天线一样，它们接收来自其他细胞和周围环境的信号，并帮助细胞做出适当的行为。这在发育过程中尤为重要，纤毛缺陷会导致一系列被称为“纤毛病”的人类发育疾病。这些疾病的范围从涉及包括大脑在内的多个器官复杂缺陷的严重、致命的疾病，到遗传性进行性视力丧失的视网膜色素变性（RP）。科学家们仍然不能完全理解纤毛是如何帮助控制大脑和视网膜发育的。虽然这些情况个别罕见，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。本研究旨在鉴定纤毛病中有缺陷（“突变”）的基因，或单独或作为途径的一部分促进纤毛形成的基因。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，使我们能够评估每个人类基因对纤毛形成的贡献（“反向基因筛选”）。我们在这项工作中处于独特的地位，研究团队在这一领域有着良好的成功记录：我们与家庭、他们的临床医生和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；我们拥有合适的最先进的技术、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大的数据集，我们现在希望在目前的研究计划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，特别是我们将使用特殊的细胞系统来更紧密地模拟大脑和视网膜组织。为此，我们将使用分化为神经元前体、神经元和视网膜细胞的小鼠和人类干细胞。重要的是，这种方法使我们能够研究RP患者视网膜组织中的纤毛。鉴定纤毛形成的新基因提供了两个主要的好处。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，在疾病机制和疾病基因的正常功能方面取得了重要的、往往出乎意料的科学见解，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，其疾病机制以前尚不清楚，可能是由视网膜中有缺陷的纤毛形成引起的。更好地了解这些过程可能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变性的疾病进展。我们还期望对其他常见疾病如多囊肾病、脊柱裂和先天性心脏缺陷的病因有新的认识。

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.