Transcription factors for promoting sensory hair cell differentiation

促进感觉毛细胞分化的转录因子

• 批准号: MR/L021099/1
• 负责人: Andrew Jarman
• 金额: $ 55.53万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL021099%2F1
• 关键词: Transcription; factors; promoting; sensory; hair

Partial or complete deafness is a condition that will affect most people in time. The majority of deafness results from loss or damage of the sensory receptor cells in the inner ear, called hair cells. Once lost or damaged, mammals including humans are not able to regenerate these hair cells. There is much interest in finding ways to stimulate the inner ear to regenerate new hair cells (a process that occurs naturally in other animals such as fish and birds). The key to this is to take lessons from our understanding of the mechanisms that generate hair cells in the developing embryo. These lessons might then be applied to therapy. For example, gene therapy may be used to trigger adult hair cell regeneration directly, or cell therapy may be used in which hair cell formation is triggered in stem cells that could then be transplanted into the inner ear.Our research aims at understanding mechanisms of hair cell formation in normal development. Already, much research has been aimed at a gene called Atoh1, which produces a 'master regulator' factor that triggers hair cell formation during development; it has even been shown in animal models that Atoh1 gene therapy can induce partial regeneration of hair cells, at least in young animals. It is widely believed that Atoh1's ability to promote the generation of hair cells is dependent on other unknown 'cofactors' within the cells of the developing ear, and that lack of such cofactors restrict its function in the adult ear. Our previous work has led to the identification of promising candidates for these cofactors. We propose to show that these cofactors are required for Atoh1's function, and then to apply this information to stem cell culture systems to determine if they can help Atoh1 to trigger hair cell formation efficiently.Our research will be conducted in mouse stem cells and in zebrafish as they are convenient, relevant and well characterised models for these kinds of analysis. If successful, our findings will be applicable to human stem cell studies, leading to potential new therapeutic routes. There are also more immediate benefits to establishing protocols for hair cell formation in stem cells. Stem cells provide a source of specialised cell types in the lab that can be used for modelling disease and for testing the effects of drugs. For instance, skin cells could be taken from patients suffering from hearing diseases and lab protocols used to convert them into hair cells in a dish. These could then be studied to determine the nature of the disease and could be used to screen for therapeutically useful drugs. Overall, our research has the potential to lead to discoveries that facilitate gene therapy, stem cell therapy, and the production of lab models for disease and drug screening.

部分或完全耳聋是一种会影响大多数人的情况。大多数耳聋是由于内耳中的感觉感受器细胞（称为毛细胞）的损失或损伤造成的。一旦丢失或受损，包括人类在内的哺乳动物就无法再生这些毛细胞。人们对寻找刺激内耳再生新毛细胞的方法很感兴趣（这一过程在其他动物如鱼类和鸟类中自然发生）。关键是从我们对发育中的胚胎中产生毛细胞的机制的理解中吸取教训。这些经验可以应用于治疗。例如，基因疗法可以直接引发成年毛细胞的再生，或者细胞疗法可以在干细胞中引发毛细胞的形成，然后将其移植到内耳中。我们的研究旨在了解正常发育中毛细胞形成的机制。许多研究已经瞄准了一种名为Atoh 1的基因，该基因产生一种“主调节因子”，在发育过程中触发毛细胞的形成;甚至在动物模型中表明，Atoh 1基因治疗可以诱导毛细胞的部分再生，至少在年轻动物中是这样。人们普遍认为Atoh 1促进毛细胞生成的能力依赖于发育中的耳朵细胞内的其他未知“辅助因子”，缺乏这些辅助因子限制了其在成年耳朵中的功能。我们以前的工作已经导致这些辅因子的有前途的候选人的识别。我们建议表明，这些辅因子所需的Atoh 1的功能，然后将此信息应用于干细胞培养系统，以确定它们是否可以帮助Atoh 1触发毛细胞形成efficiently. We的研究将在小鼠干细胞和斑马鱼，因为它们是方便的，相关的和良好的特点，这些类型的分析模型进行。如果成功，我们的发现将适用于人类干细胞研究，从而导致潜在的新治疗途径。在干细胞中建立毛细胞形成的方案也有更直接的好处。干细胞在实验室中提供了一种特殊细胞类型的来源，可用于模拟疾病和测试药物的效果。例如，可以从患有听力疾病的患者身上提取皮肤细胞，并使用实验室协议将其转化为培养皿中的毛细胞。然后可以对这些进行研究，以确定疾病的性质，并可用于筛选治疗上有用的药物。总体而言，我们的研究有可能带来促进基因治疗、干细胞治疗以及疾病和药物筛选实验室模型生产的发现。