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：必须通过完整毛细胞进行机械感应转导 对于听觉和前庭感知，因此对于生存和 许多物种的交流。 哺乳动物没有证明 后胎儿再生毛细胞。 因此，毛细胞的丧失导致 深刻的感觉缺陷。 相比之下，禽类产生前庭 毛细胞在整个生命中不断，然后再生 听觉和前庭毛细胞响应损伤。 禽毛细胞 再生主要是由于细胞增殖的上调和 分化有丝分裂后细胞为毛细胞。 这些过程发生 在培养的鸟类内耳上皮中自发。 在培养的哺乳动物中 前庭器官，某些有丝分裂受到外源生长因子的刺激， 表明哺乳动物毛细胞祖细胞也有能力 划分。 但是，几乎没有实验证据表明，在哺乳动物中 有丝分裂后细胞能够分化为毛细胞。 宽阔 我的研究目标是了解细胞和分子事件 调节镶hatch小鸡中的毛细胞的产生，并应用此 知识最终刺激哺乳动物的毛细胞再生。 提出的实验将使用体内和体外方法 确定调节毛细胞再生的分子 小鸡。 尽管目前有几个小组专注于调节有丝分裂的事件 禽听觉和前庭上皮中成熟的支持细胞的 相对较少的研究旨在了解有丝分裂后细胞的方式 被指示成为毛细胞。 我将检查细胞间的作用 通过转化生长因子β（TGF（）超家族和通过 在调节毛细胞分化中的三角洲和锯齿状 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对照和 受损的禽毛细胞上皮。 TGF（ - 相关的分子显示变化 在再生过程中的表达中将添加到培养的禽毛细胞中 祖细胞并注入完整的鸟内耳，以确定它们是否 刺激毛细胞分化。 如果三角洲和锯齿的变化 伴随再生的表达，我将检查Notch的作用 通过扰动Notch表达在毛细胞分化中的信号传导 培养的鸟类毛细胞祖细胞。 对毛细胞的理解 在成熟的脊椎动物中调节分化可能会导致对 先天性耳聋的原因和治疗方法的治疗方法 听力不足。