Gene regulatory network controlling commitment to ear identity

基因调控网络控制对耳朵身份的承诺

• 批准号: 8262996
• 负责人: Marianne Bronner
• 金额: $ 53.15万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-12 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8262996
• 关键词: Accounting; Affect; Algorithms; Auditory; Binding; Bioinformatics; Biology; Birth; Candidate Disease Gene; Cell physiology; Cells; Child; Childhood; Commit; Communication; Complex; Congenital Abnormality; DNA-Protein Interaction; Data; Defect; Development; Diagnostic; Ear; Endolymph; Enhancers; Environment; Equilibrium; Etiology; Event; Fibroblast Growth Factor; Future; Gene Expression; Gene Mutation; Gene Targeting; Genes; Genetic; Genetic Counseling; Goals; Hair Cells; Hearing; Hearing Impaired Persons; Individual; Infection; Labyrinth; Lead; Modeling; Molecular; Molecular Analysis; Monitor; Multipotent Stem Cells; Mus; Mutagenesis; Newborn Infant; Organism; Otic Placodes; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Phylogenetic Analysis; Pregnancy; Presbycusis; Prevention; Process; Proteins; Regenerative Medicine; Regulator Genes; Regulatory Element; Research; Sampling; Sense Organs; Sequence Homology; Signal Pathway; Signal Transduction; Simple Epithelium; Social Interaction; Speech; Staging; Stem Cell Research; Stem cells; Technology; Testing; Time; Transcript; base; congenital deafness; data integration; deafness; design; falls; gene function; genetic analysis; genome sequencing; hearing impairment; hindbrain; human disease; in vivo; interdisciplinary approach; loss of function; mathematical model; nano-string; new technology; novel; novel strategies; progenitor; research study; response; spatial integration; tool; transcription factor

DESCRIPTION (provided by applicant): The vertebrate inner is the most complex of the sense organs responsible for hearing and balance. Yet during development it forms from a simple epithelium, the otic placode. During development of the ear, multipotent progenitor cells become progressively restricted in their potential. This process is controlled by regulatory genes whose temporal and spatial expression patterns are tightly regulated in an orchestrated gene regulatory network (GRN). We and others have established a hierarchy of events controlling the specification and determination of inner ear progenitors and identified some of the regulatory genes involved. Based on this information, we have established a preliminary network controlling these processes and designed a molecular screen to identify novel otic specifiers. We have defined co-regulated groups of genes that reflect different stages of ear specification. We will now harness genome sequence information, new technology to monitor changes in the expression of more than 100 genes simultaneously and newly developed bioinformatics tools to build up and verify the preliminary GRN. Specifically we will: " identify new genes responsive to otic inducing signals " establish the epistatic relationships between ear specific transcription factors and signaling components " isolated and characterize enhancers controlling transcription factor expression in the ear and examine direct inputs " predict common upstream regulators for genes in each synexpression group using newly developed algorithms and test the predicted regulators in vivo. This will uncover the basic GRN controlling the specification of inner ear progenitors together with its terminal target genes. In the future, this GRN will serve as a basis for studying protein-protein and protein-DNA interactions to build up a complete network, for quantitative analysis and mathematical modeling of this process, as well as a platform to discover new candidate genes for human disease affecting hearing and balance. PUBLIC HEALTH RELEVANCE: The sense of hearing is crucial for communication with our environment. In newborn babies and young children it is essential for normal development, development of social interactions and in particular for the acquisition of speech. Worldwide 1.64 children per 1000 births are born deaf or with some form of hearing impairment mainly due to inner ear defects causing sensorineuronal deafness. Congenital deafness is acquired through drugs or infection during pregnancy in 25% of affected children. In recent years, much progress has been made in identifying the etiology of other cases, in particular through large scale mutagenesis screens in mice, leading to the successful identification of many deafness genes: known genetic mutations now account for about 50% of hearing defects. However, the underlying causes of the remaining 25% are still unknown. Thus, there is clearly a need to identify novel candidate genes and to analyze their function during ear formation and their relationship to specific phenotypes. This project aims to do so by uncovering the molecular events that gradually commit multipotent, naive cells to inner ear fate. We have harnessed our understanding of the biology of the process and newly available tools for large-scale expression analysis to design a molecular screen and have now defined new factors that control inner ear specification. These are good candidates for congenital deafness. We now plan to build up a network of genes involved in this process by using newly developed bioinformatics tools combined with in vivo functional analysis. In the long term, this will lead to the development of better diagnostic tools, novel strategies for prevention of deafness and for genetic counseling and be important for stem cell research connected to age-related hearing loss.

描述(申请人提供)：脊椎动物的内部是负责听力和平衡的感觉器官中最复杂的。然而，在发育过程中，它由一种简单的上皮--耳缘胎盘--形成。在耳朵发育过程中，多能祖细胞的潜能逐渐受到限制。这一过程由调控基因控制，其时间和空间表达模式在一个编排的基因调控网络(GRN)中受到严格调控。我们和其他人已经建立了一个控制内耳祖细胞的规格和决定的事件等级，并确定了一些涉及的调控基因。基于这些信息，我们已经建立了一个控制这些过程的初步网络，并设计了一个分子筛选器来鉴定新的One说明子。我们定义了共同调节的基因组，它们反映了耳朵规格的不同阶段。我们现在将利用基因组序列信息、同时监测100多个基因表达变化的新技术以及新开发的生物信息学工具来建立和验证初步的GRN。具体地说，我们将：“识别对听觉诱导信号作出反应的新基因”，建立耳朵特异转录因子和信号组件之间的上位关系“分离并鉴定控制耳朵中转录因子表达的增强子并检查直接输入”使用新开发的算法预测每个共表达组中基因的共同上游调控因子，并在体内测试预测的调控因子。这将揭示控制内耳祖细胞规格的基本GRN及其末端靶基因。未来，该GRN将作为研究蛋白质-蛋白质和蛋白质-DNA相互作用的基础，建立一个完整的网络，对这一过程进行定量分析和数学建模，并为发现影响听力和平衡的人类疾病的新候选基因提供平台。 与公共健康相关：听觉对于与我们的环境沟通至关重要。在新生儿和幼儿中，它对于正常发育、社会互动的发展，特别是对语言的获得是必不可少的。在世界范围内，每1000名新生儿中就有1.64名出生时耳聋或患有某种形式的听力障碍，主要是由于内耳缺陷导致的感觉神经性耳聋。在25%受影响的儿童中，先天性耳聋是通过怀孕期间的药物或感染获得的。近年来，在确定其他病例的病因方面取得了很大进展，特别是通过在小鼠身上进行大规模突变筛选，成功地鉴定了许多耳聋基因：已知的基因突变目前约占听力缺陷的50%。然而，其余25%的根本原因仍不清楚。因此，显然有必要确定新的候选基因，并分析它们在穗形成过程中的功能以及它们与特定表型的关系。该项目旨在通过揭示分子事件来实现这一点，这些分子事件逐渐将多能、幼稚的细胞与内耳命运联系在一起。我们已经利用我们对这一过程的生物学的理解和最近可用的大规模表达分析工具来设计分子筛查，现在已经定义了控制内耳规格的新因素。这些都是先天性耳聋的很好的候选者。我们现在计划通过使用新开发的生物信息学工具与体内功能分析相结合，建立一个参与这一过程的基因网络。从长远来看，这将导致更好的诊断工具的开发，预防耳聋和遗传咨询的新策略，并对与年龄相关的听力损失相关的干细胞研究具有重要意义。