HAIR CELL REGENERATION--INTERCELLULAR REGULATION

毛细胞再生--细胞间调节

• 批准号: 2592860
• 负责人: Jennifer S. Stone
• 金额: $ 10.1万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2592860
• 关键词: animal genetic material tag; bromodeoxyuridine; cell cell interaction; cell differentiation; chickens; developmental genetics; developmental neurobiology; ear hair cell; gentamicins; nervous system regeneration; neurogenetics; neurotoxicology; oligonucleotides; organ culture; polymerase chain reaction; transforming growth factors

DESCRIPTION: Mechanosensory transduction via intact hair cells is necessary for auditory and vestibular perception and thus is central to survival and communication in many species. Mammals do not demonstrate the capacity to regenerate hair cells post-embryologically. Thus, loss of hair cells leads to profound sensory deficits. In contrast, avian species produce vestibular hair cells continually throughout their life time, and they regenerate auditory and vestibular hair cells in response to damage. Avian hair cell regeneration occurs primarily by up-regulation of cell proliferation and differentiation of postmitotic cells into hair cells. These processes occur spontaneously in cultured avian inner ear epithelia. In cultured mammalian vestibular organs, some mitosis is stimulated by exogenous growth factors, suggesting that mammalian hair cell progenitors also have the capacity to divide. However, there is little experimental evidence that, in mammals, postmitotic cells are able to differentiate into hair cells. The broad goals of my research are to understand the cellular and molecular events that regulate hair cell production in the post-hatch chick and to apply this knowledge to eventually stimulate hair cell regeneration in mammals. The proposed experiments will use in vivo and in vitro approaches to identify molecules that regulate hair cell regeneration in the posthatch chick. Although several groups currently focus on events regulating mitosis of mature support cells in avian auditory and vestibular epithelia, relatively few studies are aimed at understanding how postmitotic cells are instructed to become hair cells. I will examine the role of intercellular signaling via the transforming growth factor beta (TGF()superfamily and via delta and serrate in the regulation of hair cell differentiation in the mature avian inner ear. Initial experiments will examine changes in receptor and ligand genes associated with these pathways in control and damaged avian hair cell epithelia. TGF(-related molecules that show changes in expression during regeneration will be added to cultured avian hair cell progenitors and infused into the intact avian inner ear to determine if they stimulate hair cell differentiation. If changes in delta and serrate expression accompany regeneration, I will examine the role of notch signaling in hair cell differentiation by perturbing notch expression in cultured avian hair cell progenitors. An understanding of how hair cell differentiation is regulated in mature vertebrates may lead to insight into the causes of congenital deafness and to therapeutic methods for curing hearing deficits.

描述：通过完整的毛细胞进行机械感觉转导是必要的 听觉和前庭感知，因此是生存的核心， 许多物种的交流。 哺乳动物没有表现出能力， 在胚胎期后再生毛细胞。 因此，毛细胞的损失导致 严重的感官缺陷 相比之下，鸟类产生前庭 毛细胞在它们的一生中不断地再生， 听觉和前庭毛细胞对损伤的反应。 禽毛细胞 再生主要通过细胞增殖的上调发生， 有丝分裂后的细胞分化成毛细胞。 这些过程发生 在培养的禽内耳上皮细胞中自发地表达。 培养的哺乳动物 前庭器官，一些有丝分裂被外源性生长因子刺激， 这表明哺乳动物的毛细胞祖细胞也有能力 分开 然而，几乎没有实验证据表明，在哺乳动物中， 有丝分裂后的细胞能够分化成毛细胞。 广大 我的研究目标是了解细胞和分子事件 调节孵化后小鸡毛细胞的产生， 最终刺激哺乳动物毛细胞再生。 拟议的实验将使用体内和体外方法， 鉴定调节后毛细胞再生的分子 小妞 尽管目前有几个研究小组关注的是有丝分裂的调控事件， 鸟类听觉和前庭上皮中成熟的支持细胞， 相对较少的研究旨在了解有丝分裂后细胞是如何 被指示成为毛细胞。 我将研究细胞间 通过转化生长因子β（TGF β）超家族和通过 δ和锯齿在调节毛细胞分化中的作用 成熟的鸟类内耳。 最初的实验将检查 与这些途径相关的受体和配体基因在控制和 受损的鸟类毛细胞上皮 TGF β相关分子显示出变化 将在再生期间表达In添加到培养的禽类毛细胞中 并注入完整的禽内耳，以确定它们是否 刺激毛细胞分化。 如果delta和serrate发生变化， 表达伴随再生，我将研究缺口的作用 毛细胞分化中的信号传导通过干扰Notch表达 培养的禽类毛细胞祖细胞。 对毛细胞 在成熟的脊椎动物中，分化受到调节，这可能导致对 先天性耳聋的原因和治疗方法 听力缺陷