Signal transduction in TRPM5-expressing olfactory sensory neurons

表达 TRPM5 的嗅觉感觉神经元中的信号转导

• 批准号: 7429009
• 负责人: Diego Restrepo
• 金额: $ 3.86万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7429009
• 关键词: Adult; Afferent Neurons; Agonist; Alzheimer' s Disease; Applications Grants; Area; Attention; Award; Basic Science; Behavior; Behavioral; Biological Process; Biology; Biomedical Research; Brain; Calcium; Cells; Chemicals; Chemoreceptors; Chile; Clinical; Clinical Research; Collaborations; Colorado; Communication; Country; Cyclic AMP; Data; Developed Countries; Developing Countries; Disease; Electrophysiology (science); Employee Strikes; Ensure; Epithelial Cells; Evaluation; FOS gene; Faculty; Fingers; Functional Imaging; Funding; Funding Agency; Future; Gene Targeting; Generations; Genetic; Genetic Polymorphism; Genotype; Goals; Grant; Health Sciences; Histologic; Image; Internet; Knock-out; Knockout Mice; Laboratories; Lesion; Letters; Link; Maps; Membrane; Methods; Molecular; Mus; Mutation; Neurobiology; Neurons; Nicotinic Agonists; Nicotinic Receptors; Nose; Octodon degus; Odors; Olfactory Epithelium; Patch-Clamp Techniques; Pathology; Performance; Phase I Clinical Trials; Phenotype; Pheromone; Physiological; Play; Population; Process; Program Research Project Grants; Property; Public Health; Publishing; Qualifying; Range; Research; Research Training; Rest; Rodent; Role; Schizophrenia; Science; Scientist; Signal Transduction; Smell Perception; Source; Spatial Distribution; Staging System; Students; System; Technology; Testing; Training; Transgenic Animals; Trigeminal System; United States National Institutes of Health; Universities; Urine; Week; Work; base; day; endophenotype; insight; interest; mouse model; olfactory bulb; parent grant; patch clamp; postnatal; programs; promoter; rat Gnat3 protein; receptor; receptor expression; relating to nervous system; research and development; research study; response; sensory system; systems research; tool; vomeronasal organ

DESCRIPTION (provided by applicant): Pheromones stimulate some olfactory sensory neurons (OSNs) in the main olfactory epithelium (MOE), but the transduction mechanism is poorly understood. In recent work in the Restrepo laboratory we show that signal transduction for pheromones and other biologically relevant odors in the MOE involves the transient receptor potential channel M5 (TRPM5). Interestingly, TRPM5-expressing OSNs project to urine- and pheromone-responsive areas in the ventral olfactory bulb. In addition, we find that TRPM5-positive glomeruli respond to biologically relevant odors. Our data suggest that TRPM5 is involved in pheromone transduction, but the molecular mechanism for this postulated role is unknown. In this FIRCA proposal we propose to test the hypothesis that TRPM5 is involved in pheromone signal transduction in the main olfactory epithelium through electrophysiological and calcium imaging experiments. The proposal is a collaboration between the laboratories of Juan Bacigalupo at the University of Chile and the laboratory of Diego Restrepo at the University of Colorado at Denver and Health Sciences Center. We take advantage of the fact that the expertise of the Bacigalupo laboratory in patch clamp electrophysiology is highly complementary to the expertise of the Restrepo laboratory in calcium imaging and mouse genetics. Public Health Relevance: One of the key aspects of implementing a research program to study the molecular basis of disease in a developing country is ensuring strong basic science research and training. In addition, it is important to link basic science groups with scientists working on the molecular basis and clinical aspects of disease. This basic science proposal contributes significantly to these two important aspects of successful biomedical research. The Department of Biology at the University of Chile is among the premier biology departments in Chile. Graduates from this program contribute substantially to research in the molecular basis of disease and faculty from this department undertake or collaborate in projects on the molecular basis of disease. This project will introduce the Bacigalupo laboratory to the generation and use of gene- targeted mice. It is important to indicate that the generation of gene-targeted mice, an important tool in the understanding of biological function, is only starting to be developed in Chile. The Centro de Estudios Cientificos de Valdivia (CECS, http://www.cecs.cl/web/) has been pioneering this effort, but there is little work on generation of gene-targeted mice elsewhere in the country. The award of this grant would result in training of a talented graduate student in generation of gene-targeted mice. In addition, Dr. Restrepo would give a one week course on the use of gene-targeted mice in the study of neural disease at the University of Chile. Because of the interest of both groups in gene-targeted mice, we expect future interactions between the CECS and the Bacigalupo laboratory. Indeed, there already are close ties between the two groups due to common interests on different aspects of neurobiology. Thus, this FIRCA project would strengthen basic science research and training and therefore will provide a substantial contribution to research capacity building in Chile. Another aspect important for the development of research into disease is the formation of a strong link between basic and clinical research. The qualifying grant of this FIRCA application is an NIMH-funded Conte Center grant focused on the study of schizophrenia (see Specific Aims). The overarching hypothesis is that reduced levels of alfa7 nicotinic acetylcholine receptor in the brains of schizophrenics, caused by polymorphism in the alfa7 receptor promoter, are the cause of certain endophenotypes of this disease. The Conte Center grant spans research ranging from basic to a phase I trial of DMBXA, a partial agonist of the alfa7 receptor. Dr. Restrepo's project studies changes in olfactory ability (an endophenotype in schizophrenia) as well as problems with multimodal interactions that result in decreased attention and decreased performance in goal-oriented tasks in schizophrenics. Gene- targeted mice are used in this research and olfaction is targeted as a sensory system for research because mice use this system to communicate (through pheromones and other volatile chemicals). Research in other Restrepo grants focused on the more basic aspects of olfaction have already resulted in important insights that we have been able to apply to the study of endophenotypes of schizophrenia. From our published work and other preliminary experiments that show that there is no expression of TRPM5 in OSNs until postnatal day 15th we know that TRPM5 is important in mouse chemical communication in the adult. Since chemical communication is key in studying endophenotypes of mouse models of schizophrenia, we expect that the FIRCA grant will also result in generation of information relevant to the qualifying grant. Importantly, Drs. Bacigalupo and Restrepo are also involved in a project that attempts to link basic science research with disease-oriented research in Chile. They are both part of a grant application for a supplement to "Proyecto de Anillos", sent to FONDECYT (Chilean Funding Agency for Science and Technology) the for evaluation with Dr. Adrian Palacios of Valparaiso University as the Program Director. The project is centered on the study of Alzheimer's disease using the Octodon degus, a rodent that presents a senile phenotype with striking parallels to Alzheimer's. A decrease in olfactory ability is a hallmark of Alzheimer's and because the olfactory system is relatively simple in its first processing stages, this system can be used to study the pathology of the disease. We expect that the work in our FIRCA grant application would provide information relevant to the "Proyecto de Anillos". Thus, the FIRCA application would contribute to the link between basic science and clinically oriented research in the US and Chile.

描述（由申请人提供）：信息素刺激主嗅上皮（MOE）中的一些嗅觉感觉神经元（OSNs），但其转导机制尚不清楚。在Restrepo实验室最近的工作中，我们发现信息素和其他生物相关气味的信号转导涉及瞬时受体电位通道M5 （TRPM5）。有趣的是，表达trpm5的osn投射到腹侧嗅球的尿液和信息素响应区域。此外，我们发现trpm5阳性肾小球对生物相关气味有反应。我们的数据表明，TRPM5参与信息素的转导，但这种假设作用的分子机制尚不清楚。在本FIRCA提案中，我们建议通过电生理和钙成像实验来验证TRPM5参与主嗅上皮信息素信号转导的假设。该提案是智利大学的Juan Bacigalupo实验室和丹佛科罗拉多大学的Diego Restrepo实验室以及健康科学中心的合作成果。我们利用Bacigalupo实验室在膜片钳电生理学方面的专业知识与Restrepo实验室在钙成像和小鼠遗传学方面的专业知识高度互补的事实。公共卫生相关性：在发展中国家实施研究疾病分子基础的研究计划的一个关键方面是确保强有力的基础科学研究和培训。此外，将基础科学小组与研究疾病分子基础和临床方面的科学家联系起来也很重要。这一基础科学提案对成功的生物医学研究的这两个重要方面作出了重大贡献。智利大学的生物系是智利首屈一指的生物系之一。该课程的毕业生为疾病分子基础的研究做出了重大贡献，该部门的教师承担或合作进行疾病分子基础的项目。该项目将介绍Bacigalupo实验室的基因靶向小鼠的产生和使用。重要的是要指出，基因靶向小鼠的产生是理解生物功能的重要工具，在智利才刚刚开始发展。瓦尔迪维亚科学研究中心（CECS, http://www.cecs.cl/web/）一直是这项工作的先驱，但在该国其他地方，关于基因靶向小鼠的产生的工作很少。这笔拨款将用于培养一名有才华的研究生，培养基因靶向小鼠。此外，Restrepo博士还将在智利大学（University of Chile）开设为期一周的课程，讲解基因靶向小鼠在神经疾病研究中的应用。由于两组都对基因靶向小鼠感兴趣，我们期望CECS和Bacigalupo实验室之间未来的相互作用。事实上，由于在神经生物学的不同方面有共同的兴趣，这两个小组之间已经有了密切的联系。因此，这个FIRCA项目将加强基础科学研究和培训，因此将对智利的研究能力建设作出重大贡献。疾病研究发展的另一个重要方面是在基础研究和临床研究之间形成强有力的联系。本次FIRCA申请的合格拨款是nimh资助的专注于精神分裂症研究的Conte Center拨款（见具体目标）。总的假设是，精神分裂症患者大脑中alfa7尼古丁乙酰胆碱受体水平的降低，是由alfa7受体启动子多态性引起的，是这种疾病的某些内表型的原因。Conte中心的资助涵盖了从基础研究到DMBXA（一种alfa7受体的部分激动剂）的I期试验。Restrepo博士的项目研究了嗅觉能力（精神分裂症的一种内表型）的变化，以及导致精神分裂症患者在目标导向任务中注意力下降和表现下降的多模态相互作用问题。基因靶向小鼠被用于这项研究，嗅觉被作为一种感官系统进行研究，因为小鼠使用这一系统进行交流（通过信息素和其他挥发性化学物质）。Restrepo资助的其他研究集中在嗅觉的更基本方面，已经产生了重要的见解，我们已经能够应用于精神分裂症的内表型研究。从我们发表的工作和其他初步实验表明，直到出生后15天，osn中才有TRPM5的表达，我们知道TRPM5在成年小鼠的化学通讯中很重要。由于化学通讯是研究精神分裂症小鼠模型内表型的关键，我们期望FIRCA资助也将产生与合格资助相关的信息。重要的是,Drs。Bacigalupo和Restrepo还参与了一个项目，该项目试图将智利的基础科学研究与面向疾病的研究联系起来。它们都是“Anillos项目”补充拨款申请的一部分，该项目已发送给智利科学技术资助机构（FONDECYT），由瓦尔帕莱索大学的Adrian Palacios博士担任项目主任。该项目以研究阿尔茨海默氏症为中心，使用八齿猴，一种呈现出与阿尔茨海默氏症惊人相似的衰老表型的啮齿动物。嗅觉能力下降是阿尔茨海默氏症的一个标志，由于嗅觉系统在其最初处理阶段相对简单，因此该系统可用于研究该疾病的病理。我们希望FIRCA拨款申请中的工作能够提供与“Anillos项目”相关的信息。因此，FIRCA的申请将有助于美国和智利的基础科学和临床导向研究之间的联系。