Regulation of Olfactory Signal Transduction

嗅觉信号转导的调节

• 批准号: 7466760
• 负责人: HAIQING ZHAO
• 金额: $ 40.03万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-27 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7466760
• 关键词: Affect; Afferent Neurons; Animal Behavior; Animal Model; Animals; Behavior; Behavioral; Binding; Binding Sites; Brain; Calmodulin; Cells; Characteristics; Cilia; Classification; Cyclic AMP; Cyclic Nucleotides; Detection; Discrimination; Enzymes; Feedback; Functional disorder; G-Protein-Coupled Receptors; Goals; In Vitro; Individual; Investigation; Kinetics; Knockout Mice; Knowledge; Lead; Localized; Mediating; Membrane Potentials; Molecular; Molecular Genetics; Mouse Strains; Mus; Mutation; Odors; Partner in relationship; Pathway interactions; Perception; Physiological; Physiology; Play; Process; Property; Proteins; Regulation; Research; Role; Sensory; Signal Transduction; Smell Perception; Social Interaction; System; Testing; Thinking; Time; cyclic-nucleotide gated ion channels; feeding; in vivo; insight; mouse model; phosphoric diester hydrolase; research study; response; role model; sensory system

DESCRIPTION (provided by applicant): The long-term goal of this research is to elucidate molecular mechanisms underlying sensory perception. Specifically, we seek in this proposal to understand how Ca2+ feedback mechanisms regulate olfactory sensory neuron (OSN) function in vivo and how these mechanisms contribute to the ability of the animal to detect and discriminate odors. Ca2+ plays a central role in regulating OSN responses by modulating several signal transduction proteins via calmodulin (CaM). Previous in vitro studies have implicated the olfactory cyclic nucleotide-gated (CNG) channel and phosphodiesterase 1C (PDE1C) as major targets of Ca2+/CaM. However, the functional significance of these Ca2+/CaM-target interactions in OSN physiology and olfactory behavior has not been determined. We are employing molecular genetics to specifically eliminate Ca2+/CaM binding sites in the CNG channel and PDE1C. This approach allows a systematic analysis of the role of Ca2+/CaM in regulating OSN physiology, and ultimately olfactory behavior. In Specific Aim 1 we will determine the contribution of individual CaM-binding domains of the CNG channel to Ca2+/CaM regulation of OSN responses. Specific Aim 2 seeks to delineate how the basal activity and Ca2+/CaM-stimulated activity of PDE1C independently regulate OSN responses. In Specific Aim 3, we will investigate how regulation of OSN physiology aids olfactory behaviors such as odor tracking and discrimination. The proposed experiments will lead to a better understanding of the connection from regulation of signal transduction proteins to OSN physiology, and to olfactory behavior. This knowledge will further our understanding of normal olfactory function and olfactory dysfunctions, and will provide insight into principles common to all sensory systems. This research aims to understand how regulation of key proteins in the odor-detecting cells influences the sense of smell. The knowledge from these studies will add to our understanding of both the normal function of the olfactory system and olfactory dysfunctions.

描述（由申请人提供）：本研究的长期目标是阐明感觉感知的分子机制。具体来说，我们寻求在这个建议，以了解钙离子反馈机制如何调节嗅觉感觉神经元（OSN）在体内的功能，以及这些机制如何有助于动物的能力，检测和辨别气味。Ca ~（2+）通过钙调蛋白（CaM）调节多种信号转导蛋白，在OSN反应中起重要作用。以前的体外研究表明，嗅觉环核苷酸门控（CNG）通道和磷酸二酯酶1C（PDE 1C）是Ca 2 +/CaM的主要靶点。然而，这些Ca 2 +/CaM靶相互作用在OSN生理学和嗅觉行为中的功能意义尚未确定。我们正在采用分子遗传学来特异性消除CNG通道和PDE 1C中的Ca 2 +/CaM结合位点。这种方法允许系统分析的作用，Ca 2 +/CaM调节OSN生理，并最终嗅觉行为。在具体目标1中，我们将确定CNG通道的单个CaM结合结构域对OSN响应的Ca 2 +/CaM调节的贡献。具体目标2旨在描述PDE 1C的基础活性和Ca 2 +/CaM刺激活性如何独立调节OSN反应。在具体目标3中，我们将研究OSN生理学的调节如何帮助嗅觉行为，如气味跟踪和辨别。这些实验将有助于我们更好地理解信号转导蛋白调控与嗅觉神经元生理和嗅觉行为之间的关系。这些知识将进一步加深我们对正常嗅觉功能和嗅觉功能障碍的理解，并将提供对所有感觉系统共同原理的洞察。这项研究旨在了解气味检测细胞中关键蛋白质的调节如何影响嗅觉。这些研究的知识将增加我们对嗅觉系统正常功能和嗅觉功能障碍的理解。