Role of microRNAs in mammalian ear development and neurosensory specification

描述(由申请人提供)：大量工作确立了蛋白质编码基因及其产物在耳朵和神经感觉功能发育中的作用。此外，RNA生物学的最新进展已经坚定地确立了非编码RNA作为影响发育过程的调节分子的重要性。MicroRNAs(MiRNAs)代表一大类小的非编码RNA，其功能是抑制互补靶基因的表达。某些miRNAs被证明是细胞增殖、分化和命运指定的调节者，最终影响各种生物的形态发生、组织发生和器官发生。我们发表的数据建立了对哺乳动物耳朵中miRNAs的发育表达模式和生物学功能知之甚少的信息。我们的长期目标是通过表征miRNA在发育中的小鼠内耳的表达和功能来了解miRNAs如何与耳朵生物学交叉，并实施基于miRNA的治疗策略，旨在维持或恢复对听力至关重要的细胞功能。我们之前的研究已经揭示了小鼠内耳表达的miRNAs的补体，并证明了神经感觉细胞特异性的miRNA表达。目前这一应用的具体目标是1)表征与耳朵生物学相关的miRNAs的表达模式，2)阐明miRNAs在神经感觉上皮发育和维持中的需求，以及3)确定特定的毛细胞miRNA在发育和维持中的功能。作为刺激神经感觉细胞再生和恢复听力进步的治疗途径，它们可能会从基于miRNA的策略中受益匪浅，这些策略引导新的细胞群体走向正常的神经感觉细胞功能。听力损失和耳聋的一个主要原因是衰老、感染、有毒药物或过度刺激导致的感觉细胞死亡。这项拟议的研究将确定microRNA基因在正常耳朵发育和感觉细胞功能中的作用。了解这些小RNA是如何影响这些过程的，预计将影响旨在再生感觉细胞和恢复听力的分子治疗策略。

DESCRIPTION (provided by applicant): An extensive body of work establishes the role of protein-coding genes and their products in development of the ear and neurosensory function. In addition, recent advances in RNA biology have firmly established the importance of non-coding RNAs as regulatory molecules affecting developmental processes. MicroRNAs (miRNAs) represent a large class of small non-coding RNAs that function to repress the expression of complementary target genes. Certain miRNAs are demonstrated regulators of cellular proliferation, differentiation and fate specification that ultimately affect morphogenesis, histogenesis and organogenesis in a variety of organisms. Our published data has established the little that is known about the developmental expression patterns and biological functions of miRNAs in the mammalian ear. Our long-term objectives are to understand how miRNAs intersect ear biology by characterizing miRNA expression and function in the developing mouse inner ear, and to implement miRNA-based therapeutic strategies designed to maintain or restore cellular functions crucial to hearing. Our previous studies have revealed the complement of miRNAs expressed in the mouse inner ear and have demonstrated neurosensory cell- specific miRNA expression. The specific aims of this current application seek to 1) characterize the expression patterns of miRNAs that are relevant to ear biology, 2) demonstrate the requirement of miRNAs in neurosensory epithelial development and maintenance, and 3) determine specific hair cell miRNA functions in development and maintenance. As therapeutic avenues for stimulating neurosensory cell regeneration and restoring hearing progress, they might benefit substantially from miRNA-based strategies that guide new cell populations toward normal neurosensory cell functions. A major cause of hearing loss and deafness is sensory cell death resulting from aging, infections, toxic drugs, or overstimulation. The proposed research will determine the roles of microRNA genes in normal ear development and sensory cell function. Understanding how these small RNAs influence such processes is expected to impact molecular therapeutic strategies designed to regenerate sensory cells and restoring hearing.