Role of microRNAs in mammalian ear development and neurosensory specification

描述（由申请人提供）：大量的工作建立了蛋白质编码基因及其产物在耳朵和神经感觉功能发展中的作用。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）代表了一类小的非编码rna，其功能是抑制互补靶基因的表达。某些mirna被证明是细胞增殖、分化和命运规范的调节剂，最终影响多种生物的形态发生、组织发生和器官发生。我们发表的数据已经建立了对哺乳动物耳朵中mirna的发育表达模式和生物学功能知之甚少。我们的长期目标是通过表征发育中的小鼠内耳中的miRNA表达和功能来了解miRNA如何与耳部生物学交叉，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中表达的miRNA的补体，并证实了神经感觉细胞特异性miRNA的表达。本应用的具体目的是寻求1)表征与耳生物学相关的miRNA的表达模式，2)证明miRNA在神经感觉上皮发育和维持中的需求，以及3)确定毛细胞miRNA在发育和维持中的特定功能。作为刺激神经感觉细胞再生和恢复听力进展的治疗途径，它们可能会从基于mirna的策略中获益，这些策略可以引导新细胞群走向正常的神经感觉细胞功能。听力损失和耳聋的主要原因是由衰老、感染、有毒药物或过度刺激引起的感觉细胞死亡。拟议的研究将确定microRNA基因在正常耳发育和感觉细胞功能中的作用。了解这些小rna如何影响这些过程有望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.