NADPH Oxidase Complexes in Mammalian Vestibular Function

NADPH 氧化酶复合物在哺乳动物前庭功能中的作用

• 批准号: 7151991
• 负责人: DAVID ERIC BERGSTROM
• 金额: $ 28.55万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-05 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7151991
• 关键词: Acceleration; Affect; Age; American; Attention; Candidate Disease Gene; Caring; Cell physiology; Cells; Complex; Condition; Development; Disease; Disruption; Dizziness; Equilibrium; Fall prevention; Family; Force of Gravity; Foundations; Fracture; Functional disorder; Gene Targeting; Genes; Grant; Head; Health; Immune; Individual; Invaded; Labyrinth; Lead; Life Style; Medical; Molecular; Molecular Genetics; Mood Disorders; Mus; Mutagenesis; Mutant Strains Mice; NADP; NADPH Oxidase; Names; Oxidases; Pan Genus; Pan troglodytes; Pathology; Pathway interactions; Phagocytes; Physiology; Play; Principal Investigator; Production; Proteins; Public Health; Range; Rattus; Reactive Oxygen Species; Regulatory Element; Role; Sequence Analysis; Sequence Homology; Signal Transduction; Structure; Symptoms; System; Transcriptional Regulation; Transgenes; Vertigo; Vestibular Diseases; Vision; Walking; Yeasts; cost; design; falls; improved; insight; killings; knockout gene; macula; man; member; microorganism; mind control; mouse model; mutant; paralogous gene; positional cloning; protein protein interaction; research study; response; transcription factor; yeast two hybrid system

DESCRIPTION (provided by applicant): 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, calledotoconia, that are required to detect linear acceleration and gravity. Sequence similarity of Nox3 and Noxolto 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 investibular 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 ofNox3 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.

描述（由申请人提供）：前庭（平衡）障碍是美国公众严重的健康问题。虽然前庭功能障碍在老年人中最常见，但它可以影响所有年龄段的人。事实上，失衡症状是美国人每年花费超过10亿美元寻求医疗保健的25大原因之一。前庭疾病的后果范围从视力、肌肉和情绪障碍到福尔斯和骨折。随着美国人在晚年继续过着更积极的生活方式，前庭疾病的后果可能会更加突出。 为了提高我们对前庭系统功能的理解，我们使用定位克隆策略来鉴定Nox 3和Noxol，分别作为头倾斜（het）和头倾斜（hslt）小鼠模型的致病基因。这两种前庭突变体在内耳中缺乏检测线性加速度和重力所需的关键结构，即耳锥。Nox 3和Noxolto已知基因的序列相似性强烈表明这些基因编码在前庭系统内活跃的NADPH氧化酶复合物的两个成员。 在本研究中，我们的目标是：（1）利用酵母双杂交和计算方法鉴定NOX 3/NOXO 1复合物中的其他基因产物;（2）通过在小鼠中建立靶向基因敲除，并通过电生理学评估其前庭功能，阐明这些基因产物在前庭功能中的作用;（3）通过对预测的Nox 3调控元件的转基因分析，增加我们对Nox 3上游分子遗传途径的理解。 总之，这些实验将为控制这一重要脊椎动物系统的发育、生理和病理的分子和细胞过程提供新的见解。 与公共卫生的关系：健康人直立行走和保持平衡的能力是由大脑和它从内耳前庭（平衡）系统接收的信号控制的。在拟议的实验中，首席研究员的目标是识别和研究控制前庭系统发育和功能的新基因。通过更好地了解前庭系统，将建立一个基础，以开发更好的治疗眩晕和头晕等疾病，以期防止福尔斯和骨折。