MECHANISMS OF SENSORY REGENERATION

感觉再生的机制

• 批准号: 7915256
• 负责人: Mark Warchol
• 金额: $ 38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7915256
• 关键词: Acoustic Trauma; Biological; Biological Models; Birds; Cell Adhesion Molecules; Cell Polarity; Cell Transplants; Cells; Characteristics; Cochlea; Data; Development; Ear; Epithelium; Fibroblast Growth Factor; Gene Expression; Generations; Goals; Hair Cells; Hearing; Hearing problem; Human; In Vitro; Injury; Knowledge; Labyrinth; Mammals; Mechanics; Methods; Molecular Profiling; Mus; Natural regeneration; Organ; Organ Culture Techniques; Organ of Corti; Pattern; Pattern Formation; Phenotype; Population; Process; Recovery; Recovery of Function; Research Project Grants; Role; Scheme; Sensory; Sensory Hair; Series; Signal Pathway; Signal Transduction; Signaling Molecule; Sonic Hedgehog Pathway; Stem cells; Stereocilium; Stimulus; Testing; Time; Transcription Factor 3; Transfection; Transplantation; Type I Hair Cell; Type II Hair Cell; Utricle structure; Vertebrates; Vestibular Hair Cells; Viral; Work; base; computerized data processing; equilibration disorder; injured; notch protein; regenerative; repaired; research study; sensory mechanism; stress-activated protein kinase 1; tectorial membrane; transcription factor

The loss of sensory hair cells from the human ear is a leading cause of hearing and balance disorders. Although the potential for regeneration in the human ear is very limited, the ears of nonmammalian vertebrates can quickly regenerate after injury. A detailed understanding of the biological basis of this repair process should suggest methods for promoting similar forms of regeneration in humans. The overall goals of this study are to identify the biological signals that regulate hair cell phenotype and orientation during regeneration. One project will focus on the differentiation of vestibular hair cells. It has been known for over 50 years that the vestibular organs of higher vertebrates contain two distinct classes of sensory hair cell (which are known as type I and type II), yet we know nothing about the developmental origin of these two cell classes. Using newly-described markers for these cells, we will carry-out a quantitative characterization of the recovery of type I and type II hair cells during regeneration. A second project will examine how hair cell stereocilia reacquire their proper orientation during regeneration. We have found that regenerated hair cells in organ cultures of the avian ear are normally-oriented and our preliminary data suggest that molecules of the planar cell polarity (PCP) signaling pathway are critically involved in this process. A series of experiments will use in vitro methods to directly test the role of PCP signaling in regeneration. Finally, we will carry-out a detailed study of changes in the expression of core PCP molecules in the mammalian cochlea after ototoxic injury. Such knowledge will be crucial to all current efforts aimed at the induction of biological repair in the mammalian inner ear.

人类耳朵上感觉毛细胞的丧失是导致听力和平衡障碍的主要原因。虽然人类耳朵的再生潜力非常有限，但非哺乳动物脊椎动物的耳朵在受伤后可以很快再生。对这种修复过程的生物学基础的详细了解应该会为促进人类类似形式的再生提供方法。这项研究的总体目标是确定在再生过程中调节毛细胞表型和方向的生物信号。其中一个项目将专注于前庭毛细胞的分化。高等脊椎动物的前庭器官含有两类不同的感觉毛细胞(称为I型和II型)已有50多年的历史，但我们对这两类细胞的发育起源一无所知。使用新描述的这些细胞的标记，我们将对再生过程中I型和II型毛细胞的恢复进行定量表征。第二个项目将研究毛细胞立体纤毛如何在再生过程中重新获得正确的方向。我们发现在禽耳的器官培养中再生的毛细胞是正常定向的，我们的初步数据表明平面细胞极性(PCP)信号通路的分子在这一过程中起着关键作用。一系列实验将使用体外方法直接测试PCP信号在再生中的作用。最后，我们将对哺乳动物耳毒性损伤后耳蜗核心PCP分子表达的变化进行详细的研究。这些知识对于目前旨在诱导哺乳动物内耳生物修复的所有努力都是至关重要的。