Regulation of Olfactory Signal Transduction

嗅觉信号转导的调节

• 批准号: 8213440
• 负责人: HAIQING ZHAO
• 金额: $ 36.16万
• 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/8213440
• 关键词: Affect; Afferent Neurons; Animal Behavior; Animal Model; Animals; Behavior; Behavioral; Binding; Binding Sites; Brain; Calmodulin; Cells; Characteristics; Cilia; Cyclic AMP; Cyclic Nucleotides; Detection; Discrimination; Enzymes; Feedback; Functional disorder; G-Protein-Coupled Receptors; Goals; In Vitro; Individual; Investigation; Kinetics; Knockout Mice; Knowledge; Lead; 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; 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）：这项研究的长期目标是阐明感觉感知的分子机制。具体而言，我们在此提案中寻求了解CA2+反馈机制如何调节体内嗅觉感觉神经元（OSN）功能，以及这些机制如何有助于动物检测和区分气味的能力。 Ca2+通过通过钙调蛋白（CAM）调节几种信号转导蛋白来调节OSN响应的核心作用。先前的体外研究已将嗅觉环状核苷酸门控通道和磷酸二酯酶1C（PDE1C）作为CA2+/CAM的主要靶标。但是，尚未确定这些CA2+/CAM-TARGET相互作用在OSN生理和嗅觉行为中的功能意义。我们正在使用分子遗传学来特异性消除CNG通道和PDE1C中的Ca2+/CAM结合位点。这种方法可以系统地分析Ca2+/CAM在调节OSN生理学以及最终嗅觉行为中的作用。在特定目标1中，我们将确定CNG通道的单个C​​AM结合域对CA2+/CAM调节OSN响应的贡献。特定的目标2试图描述如何独立调节OSN响应的PDE1C的基础活性和Ca2+/CAM刺激的活性。在特定目标3中，我们将调查OSN生理学的调节如何有助于嗅觉行为，例如气味跟踪和歧视。提出的实验将使人们更好地理解从信号转导蛋白到OSN生理学以及嗅觉行为的连接。这些知识将进一步了解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见解。这项研究旨在了解气味探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的正常功能和嗅觉功能障碍的理解。