Transcription factors for promoting sensory hair cell differentiation

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感觉受体细胞（称为毛细胞）的丢失或损伤造成的。一旦毛细胞丢失或受损，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（这一过程在鱼类和鸟类等其他动物中自然发生）。解决这个问题的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。这些经验可能会应用到治疗中。例如，基因疗法可用于直接触发成人毛细胞再生，或者细胞疗法可用于在干细胞中触发毛细胞形成，然后将其移植到内耳。我们的研究旨在了解正常发育过程中毛细胞形成的机制。已经有很多研究针对一种名为Atoh1的基因，这种基因产生一种“主调节”因子，在发育过程中触发毛细胞的形成；甚至在动物模型中显示，Atoh1基因疗法可以诱导毛细胞的部分再生，至少在年轻的动物中是这样。人们普遍认为，Atoh1促进毛细胞生成的能力依赖于发育中的耳朵细胞中其他未知的“辅助因子”，而缺乏这些辅助因子限制了它在成年耳朵中的功能。我们之前的工作已经确定了这些辅因子的有希望的候选者。我们建议证明这些辅助因子是Atoh1功能所必需的，然后将这些信息应用于干细胞培养系统，以确定它们是否可以帮助Atoh1有效地触发毛细胞形成。我们的研究将在小鼠干细胞和斑马鱼中进行，因为它们是这些分析的方便、相关和特征良好的模型。如果成功，我们的发现将适用于人类干细胞研究，带来潜在的新治疗途径。建立干细胞中毛细胞形成的规程也有更直接的好处。干细胞为实验室提供了特化细胞类型的来源，可用于疾病建模和药物效果测试。例如，可以从患有听力疾病的患者身上提取皮肤细胞，并使用实验室规程将其在培养皿中转化为毛细胞。然后可以对这些进行研究，以确定疾病的性质，并可用于筛选治疗有用的药物。总的来说，我们的研究有可能促进基因治疗、干细胞治疗以及疾病和药物筛选实验室模型的产生。

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.