NADPH Oxidase Complexes in Mammalian Vestibular Function

前庭(平衡)障碍是美国公众的一个严重的健康问题。尽管大多数 前庭功能障碍在老年人中占主导地位，可影响所有年龄段的人。事实上, 失衡症状是美国人寻求医疗保健的25大原因之一，费用超过 每年10亿美元。前庭疾病的后果包括视力、肌肉和情绪。 从失足到跌倒和骨折。随着美国人晚年继续过着更加活跃的生活方式， 前庭疾病的后果可以预期会变得更加突出。 为了提高我们对前庭系统功能的理解，我们使用了位置克隆策略 确定nox3和noxol是导致头部倾斜(Het)和头部倾斜(Hslt)的基因 分别建立小鼠模型。这两个前庭突变体在内耳中缺乏关键结构，称为 耳锥，这是检测线加速度和重力所必需的。Nox3和Noxol的序列相似性 已知基因强烈提示这些基因编码NADPH氧化酶复合体的两个成员 活跃在前庭系统内。 在拟议的研究中，我们的目标是(1)使用酵母双杂交和计算方法来鉴定 NOX3/NOXO1复合体中的其他基因产物；(2)阐明这些基因产物在 在小鼠中创建靶向基因敲除并评估其前庭功能的前庭功能 电生理学；以及(3)增加我们对基因上游分子遗传途径的理解 利用转基因分析预测的NOX3调控元件。 总之，这些实验将为分子和细胞过程提供新的见解。 控制这一重要脊椎动物系统的发育、生理和病理。 与公共健康的相关性：健康的个人直立行走和保持 平衡是由大脑和它从内耳前庭接收的信号控制的 (平衡)制度。在拟议的实验中，首席调查员的目标是识别和研究新的 控制前庭系统发育和功能的基因。通过更好地理解 前庭系统，将建立一个基金会，以开发更好的治疗方法，如 眩晕和眩晕，希望能防止摔倒和骨折。

Vestibular (balance) disorders represent a serious health problem for the American public. Although most predominant among older individuals, vestibular dysfunction can affect people of all ages. In fact, imbalance symptoms represent one of the top 25 reasons Americans seek medical care at a cost of over $1 billion per year. The consequences of vestibular disease range from vision, muscular, and mood disorders to falls and fractures. As Americans continue to lead more active lifestyles in their later years, the consequences of vestibular disease can be expected to take on added prominence. To improve our understanding of vestibular system function, we have used positional cloning strategies to identify Nox3 and Noxol, as the causative genes underlying the head tilt (het) and head slant (hslt) mouse models, respectively. These two vestibular mutants lack critical structures in the inner ear, called otoconia, that are required to detect linear acceleration and gravity. Sequence similarity of Nox3 and Noxol to known genes strongly suggests that these genes encode two members of an NADPH oxidase complex active within the vestibular system. In the proposed studies, we aim to (1) use yeast two-hybrid and computational approaches to identify other gene products within the NOX3/NOXO1 complex; (2) elucidate the role of these gene products in vestibular function by creating targeted gene knockouts in mice, and assessing their vestibular function electrophysiologically; and (3) increase our understanding of the molecular genetic pathways upstream of Nox3 using transgene analysis of predicted Nox3 regulatory elements. Together, these experiments will provide new insights into the molecular and cellular processes controlling the development, physiology, and pathology of this important vertebrate system. RELEVANCE TO PUBLIC HEALTH: The ability of healthy individuals to walk upright and maintain balance is controlled by the brain and by signals that it receives from within the inner ear's vestibular (balance) system. In the proposed experiments, the Principal Investigator aims to identify and study new genes controlling the development and function of the vestibular system. By better understanding the vestibular system, a foundation will be established to develop better treatments for such conditions as vertigo and dizziness in the hope of preventing falls and fractures.