Towards a predictive model for vertebrate inner ear determination

建立脊椎动物内耳测定的预测模型

• 批准号: BB/I021647/1
• 负责人: Andrea Streit
• 金额: $ 53.84万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI021647%2F1
• 关键词: Towards; predictive; model; vertebrate; inner

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.

通过语言和听觉与他人和环境交流，是儿童正常发育和健康老龄化的基础。在世界范围内，每1000名新生儿中有1.64名婴儿天生失聪，使听力障碍成为最普遍的先天性缺陷之一。同样，超过50%的60岁以上的人口受到听力问题的影响，降低了他们的生活质量以及心理和社会福祉。尽管在确定儿童耳部缺陷的基因以及了解衰老或受损耳朵中的声音感知细胞如何退化方面取得了进展，但许多相关基因仍然未知;对于那些已知的基因，它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朵形成模型，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，我们选择了一个更高级的脊椎动物模型系统，小鸡，其发展非常类似于人类的发展。我们采用了最先进的技术使这个项目成为可能，并且已经产生了一系列形成耳朵的细胞特异性基因。现在，我们将使用这个列表与文献中的数据一起构建一个计算机模型，预测不同分子如何相互作用，以及哪些分子对形成耳朵最重要。然后，我们将使用体内实验来测试这些预测，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件的行为。然后，这些信息将被反馈到模型中进行细化。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迟发性耳聋的新候选人，预测基因突变的后果，并设计策略以驱动干细胞向耳的命运或重新激活正常耳中的内在干细胞以取代受损的结构。此外，由于其预测性，将有助于减少和完善生物医学研究中的动物实验。

项目成果

Computational tools and resources for prediction and analysis of gene regulatory regions in the chick genome.

• DOI: 10.1002/dvg.22375
• 发表时间: 2013-05
• 期刊: GENESIS
• 影响因子: 1.5
• 作者: Khan, Mohsin A. F.;Soto-Jimenez, Luz Mayela;Howe, Timothy;Streit, Andrea;Sosinsky, Alona;Stern, Claudio D.
• 通讯作者: Stern, Claudio D.

Auditory hair cell defects as potential cause for sensorineural deafness in Wolf-Hirschhorn syndrome.

• DOI: 10.1242/dmm.019547
• 发表时间: 2015-09
• 期刊: Disease models & mechanisms
• 影响因子: 4.3
• 作者: Ahmed M;Ura K;Streit A
• 通讯作者: Streit A

A medium-scale assay for enhancer validation in amniotes.

• DOI: 10.1002/dvdy.24306
• 发表时间: 2015-10
• 期刊: Developmental dynamics : an official publication of the American Association of Anatomists
• 作者: Chen J;Streit A
• 通讯作者: Streit A

Experimental approaches for gene regulatory network construction: the chick as a model system.

• DOI: 10.1002/dvg.22359
• 发表时间: 2013-05
• 期刊: GENESIS
• 影响因子: 1.5
• 作者: Streit, Andrea;Tambalo, Monica;Chen, Jingchen;Grocott, Timothy;Anwar, Maryam;Sosinsky, Alona;Stern, Claudio D.
• 通讯作者: Stern, Claudio D.

A systems-level approach reveals new gene regulatory modules in the developing ear.

• DOI: 10.1242/dev.148494
• 发表时间: 2017-04-15
• 期刊: Development (Cambridge, England)
• 作者: Chen J;Tambalo M;Barembaum M;Ranganathan R;Simões-Costa M;Bronner ME;Streit A
• 通讯作者: Streit A