Towards a predictive model for vertebrate inner ear determination

通过言语和听觉与他人和我们的环境沟通是儿童正常发展和健康老龄化的基础。在世界范围内，每1000个新生儿中有1.64个天生耳聋，使听力障碍成为最普遍的先天性缺陷之一。同样，60岁以上的人口中有50%以上受到听力问题的影响，从而降低了他们的生活质量以及精神和社会福祉。尽管在确定儿童耳部缺陷的基因以及了解老化或受损耳朵中的声音感应细胞如何退化方面取得了进展，但许多相关基因仍然未知；对于那些已知的，他们的相互作用知之甚少。这是因为缺乏系统的研究，因为缺乏一个统一的耳部形成模型，该模型整合了来自不同动物模型的基因功能信息。在这里，我们建议通过结合计算工具、系统的体内实验和一种新技术来构建这样一个模型，以监测单个样品中多达200个分子的变化。为了做到这一点，我们选择了一种更高级的脊椎动物模型系统——小鸡，它的发育与人类的发育非常相似。我们采用了最先进的技术使这个项目成为可能，并且已经生成了形成耳朵的细胞的特定基因列表。现在，我们将使用这个列表和文献中的数据来构建一个计算机模型，该模型可以预测不同的分子如何相互作用，以及哪些分子对形成耳朵最重要。然后，我们将通过系统地去除每个重要因素的功能并测量模型的所有其他组成部分的行为，使用体内实验来测试这些预测。然后，这些信息将被反馈到模型中以进行细化。重复实验操作和计算机建模的循环将产生一个可靠的模型，复制胚胎中正常的耳朵形成，以解释不同分子之间的相互作用。该模型将有助于预测先天性和晚发性耳聋的新候选，预测基因突变的后果，并设计策略来驱动干细胞走向耳朵的命运或重新激活正常耳朵中的固有干细胞以取代受损的结构。此外，由于其预测性，它将有助于减少和改进生物医学研究中的动物实验。

Communication with each other and our environment through speech and hearing is fundamental for normal development of children as well as for healthy ageing. Worldwide, 1.64 babies per 1000 births are born deaf, making hearing impairment one of the most prevalent congenital defects. Likewise, more than 50% of the population over 60 is affected by hearing problems reducing their quality of life and mental and social well-being. Despite progress in identifying genes underlying ear defects in children and in understanding how sound sensing cells in the ageing or damaged ear degenerate, many of the genes responsible remain unknown; for those that are known, their interactions are poorly understood. This is because systematic studies are lacking, as is a unifying model for ear formation that integrates information about gene function from different animal models. Here we propose to construct such a model by combining a computational tool, systematic in vivo experiments and a new technology to monitor changes in up to 200 molecules in a single sample. To do this we have chosen a higher vertebrate model system, the chick, whose development closely resembles human development. We adapted state-of-the-art technology to make this project possible and have already generated a list of genes specific for cells that form the ear. Now, we will use this list together with data from the literature to construct a computer model that predicts how different molecules interact with each other and which molecules are most important to form the ear. We will then test these predictions using in vivo experiments by systematically removing the function of each important factor and measuring how all other components of the model behave. This information will then be fed back into the model for refinement. Repeating the cycle of experimental manipulation and computer modelling will generate a reliable model that replicates normal ear formation in the embryo, to explain the interactions between different molecules. This model will be useful to predict novel candidates for congenital and late-onset deafness, to predict the consequences of genetic mutations, and to design strategies to drive stem cells towards ear fate or to reactivate intrinsic stem cells in the normal ear to replace damaged structures. In addition, because of its predictive nature, it will be help to reduce and refine animal experiments in biomedical research.