Sensory Organ Formation in the Inner Ear

内耳感觉器官的形成

• 批准号: 9025772
• 负责人: Amy Kiernan
• 金额: $ 39.41万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-05 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9025772
• 关键词: Address; Adult; Affect; Alleles; Boxing; Cell physiology; Cells; Cochlea; Data; Defect; Development; Disease; Ear; Embryo; Epithelium; Event; Functional disorder; Generations; Goals; Hair Cells; Health; Hearing; In Vitro; Labyrinth; Ligands; Location; LoxP-flanked allele; Maps; Mediating; Molecular; Multipotent Stem Cells; Mus; Natural regeneration; Neurons; Notch Signaling Pathway; Organ; Organ of Corti; Pattern; Phenotype; Population; Proliferating; Replacement Therapy; Research; Research Personnel; Role; Sensory; Signal Transduction; Specific qualifier value; Supporting Cell; Testing; Time; To specify; Up-Regulation; cell type; deafness; design; ear development; gain of function; in vivo; loss of function; mutant; neurosensory; notch protein; novel; novel strategies; otoconia; postnatal; progenitor; programs; regenerative; research study; tool; transcription factor

 DESCRIPTION (provided by applicant): A large proportion of deafness and vestibular disorders are caused by loss or dysfunction of critical cell types in the inner ear, including hair cells, supporting cells and cochleovestibular neurons. Thus, in order to treat many forms of inner ear dysfunction, a thorough understanding of how these cell types form is a necessary prerequisite for designing cell regeneration or replacement therapies. Lineage studies have demonstrated that these cell types can arise from a common progenitor. Thus, one approach to regenerating or replacing these cell types is through the generation of these multipotent progenitors. The long-term goal of this research program is to understand the molecular mechanisms that control specification of the neurosensory progenitors, as well as the factors controlling the generation of the different cell types arising from these progenitors. Although we are beginning to understand some of the factors that are important in the lineage of the sensory progenitors, there are still many fundamental questions that remain unanswered, including how and when the sensory progenitors are generated. The SRY-box transcription factor SOX2 is an essential factor for sensory progenitor development. Loss of function studies in the mouse have shown that SOX2 is a critical factor for development of the sensory progenitors, as deletion of SOX2 leads to complete absence of all hair cells and supporting cells in the inner ear epithelium. However, we still have little understanding of how and when SOX2 acts in the development of these important progenitors. In this proposal we will focus on understanding how SOX2 acts to generate the sensory regions. Specifically, to define the spatial and temporal requirements for SOX2 function, we will use a newly-generated inducible mouse Cre allele to fate map SOX2-expressing cells and perform timed-deletion experiments (Aim I and II). In Aim III we will investigate whether SOX2 is capable of producing ectopic sensory regions in the postnatal and adult inner ear. Finally, we will test whether JAG1- mediated Notch signaling, which is also critical in the generation of the sensory progenitors, acts upstream of SOX2 by performing rescue experiments (Aim IV). Together, these experiments will reveal fundamental aspects of SOX2 function and further elucidate the potential of SOX2 in regenerating or replacing critical cell types in the ear through generation of the sensory progenitors.

 描述（由申请人提供）：很大一部分耳聋和前庭疾病是由内耳中关键细胞类型（包括毛发）的丢失或功能障碍引起的 细胞、支持细胞和耳蜗前庭神经元。因此，为了治疗多种形式的内耳功能障碍，彻底了解这些细胞类型如何形成是设计细胞再生或替代疗法的必要先决条件。谱系研究表明，这些细胞类型可以来自共同的祖细胞。因此，再生或替换这些细胞类型的一种方法是通过产生这些多能祖细胞。这项研究计划的长期目标是了解控制神经感觉祖细胞规格的分子机制，以及控制这些祖细胞产生不同细胞类型的因素。虽然我们开始了解感觉祖细胞谱系中的一些重要因素，但仍有许多基本问题尚未解决，包括感觉祖细胞是如何以及何时产生的。SRY盒转录因子SOX 2是感觉祖细胞发育的重要因子。在小鼠中进行的功能丧失研究表明，SOX 2是感觉祖细胞发育的关键因素，因为SOX 2的缺失导致内耳上皮中所有毛细胞和支持细胞完全缺失。然而，我们仍然对SOX 2如何以及何时在这些重要祖细胞的发育中起作用知之甚少。在这个提案中，我们将重点了解SOX 2如何产生感觉区域。具体而言，为了定义SOX 2功能的空间和时间要求，我们将使用新生成的诱导型小鼠Cre等位基因来命运映射SOX 2表达细胞并进行定时缺失实验（目的I和II）。在目的III中，我们将研究SOX 2是否能够在出生后和成人内耳中产生异位感觉区。最后，我们将测试是否JAG1介导的Notch信号，这也是在感觉祖细胞的产生，行为的上游SOX 2通过执行救援实验（目的IV）。总之，这些实验将揭示SOX 2功能的基本方面，并进一步阐明SOX 2通过产生感觉祖细胞在耳中再生或替代关键细胞类型的潜力。