MOLECULAR BASIS OF INHERITED DEAFNESS

遗传性耳聋的分子基础

• 批准号: 6345342
• 负责人: DAVID P COREY
• 金额: $ 4.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6345342
• 关键词: angiogenesis inhibitors; animal genetic material tag; antisense nucleic acid; clinical research; complementary DNA; congenital deafness; ear hair cell; enzyme activity; enzyme induction /repression; gene expression; gene mutation; human genetic material tag; human subject; isozymes; laboratory mouse; male; myosins; protein structure function; sex linked trait; tissue /cell culture

In this proposal we outline studies on three genes for inherited deafness: those encoding Norrie (Norrie disease), myosin-VIIa (Usher 1B and the shaker-1 mouse), and myosin-VIIb (a candidate for the twirler and shaker-2 mouse mutants). The Norrie studies continue work done in the first two years of t his grant, while the myosin studies initiate two new programs. Norrie disease is a rare X-linked syndromic deafness, with congenital blindness and progressive hearing loss. We have cloned the gene defective in this disease; it encodes a small, secreted protein (norrin) that my be a growth factor. The pathology in some vagrants of the disease suggest that a defective norrin allows excessive growth of blood vessels - that it isnorally an angiogenesis inhibitor. We propose several methods to test this hypothesis, and propose to initiate or continue audiometric and histological studies of both humans and mice with this defective gene. Usher 1B presents with congenial deafness and absence of vestibular function, and progressive loss of vision. It is the most common genetic deafness in humans. The gene defective encodes myosinVIIa, a protein that connects and moves other proteins on action. We have closed human myosin-VIIa, and have used antibodies to locate it in auditory receptor cells with electron microscopy. We will test a specific hypotheses that myosin-VIIA is involved in maintaining cohesion of the mechanosensitive cilia, by using a mutant mouse, shaker-1, that has defective myosin-VIIa and by using gene transfers to disrupt myosin-VIIa in normal mice. There is evidence that other myosin-VII isoforms exist in the cochlea, and that they may also cause deafness when defective. We have closed fragments of the genes and have compared their chromosomal location to genetic deafness in mice. We propose to clone these other isoforms, and to test them as candidate deafness genes.

在此提案中，我们概述了有关继承的三个基因的研究 耳聋：编码Norrie（Norrie病），肌球蛋白-VIIA的人 （Usher 1B和Shaker-1鼠标）和肌球蛋白 - VIIB（候选人 对于旋转器和摇动2小鼠突变体）。 诺里研究 继续在赠款的前两年继续完成工作，而 肌球蛋白研究启动了两个新程序。 诺里病是一种罕见的X连锁综合性耳聋，有 先天性失明和进行性听力损失。 我们有 克隆了该疾病中有缺陷的基因；它编码一个小的 分泌的蛋白质（诺林）是我的生长因子。 这 在某些疾病的某些流浪者中，病理表明有缺陷 诺林允许血管过多生长 - 它是诺 血管生成抑制剂。 我们提出了几种测试的方法 假设，并建议启动或继续听力计量学和 人类和小鼠的组织学研究 基因。 Usher 1B呈现有友善的耳聋和缺席 前庭功能和逐渐丧失视力。 这是最大的 人类常见的遗传耳聋。 基因缺陷编码 Myosinviia，一种连接并移动其他蛋白质的蛋白质 行动。 我们已经关闭了人类肌球蛋白-VIIA，并使用了 用电子将其定位在听觉受体细胞中的抗体 显微镜。 我们将测试肌球蛋白-VIIA的特定假设 参与维持机械敏感纤毛的内聚力， 通过使用肌球蛋白-VIIA有缺陷的突变鼠 并通过使用基因转移来破坏正常的肌球蛋白-VIIA 老鼠。 有证据表明，其他肌球蛋白VII同工型也存在 耳蜗，当有缺陷时它们也可能引起耳聋。 我们已经关闭了基因的碎片，并将其比较 小鼠遗传性耳聋的染色体位置。 我们建议 克隆这些其他同工型，并将其作为候选耳聋进行测试 基因。