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: 7595927
• 负责人: Diego Restrepo
• 金额: $ 3.22万
• 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/7595927
• 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; National Institute on Deafness and Other Communication Disorders; 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; Publishing; Qualifying; Research; Research Training; Rest; Rodent; Role; Schizophrenia; Science; Scientist; Signal Transduction; Smell Perception; Source; Spatial Distribution; Staging System; System; Technology; Testing; Training; Transgenic Animals; Trigeminal System; United States National Institutes of Health; Universities; Urine; Work; activity marker; base; endophenotype; graduate student; insight; interest; mouse model; olfactory bulb; parent grant; patch clamp; postnatal; programs; promoter; public health relevance; 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（OSN），但其转导机制知之甚少。在 Restrepo 实验室最近的工作中，我们表明 MOE 中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 投射到腹侧嗅球中的尿液和信息素反应区域。此外，我们发现 TRPM5 阳性肾小球对生物学相关的气味有反应。我们的数据表明 TRPM5 参与信息素转导，但这种假设作用的分子机制尚不清楚。在此 FIRCA 提案中，我们建议通过电生理学和钙成像实验来检验 TRPM5 参与主嗅上皮信息素信号转导的假设。该提案是智利大学胡安·巴西加卢波实验室和丹佛科罗拉多大学迭戈·雷斯特雷波实验室以及健康科学中心之间的合作。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关键方面之一是确保强有力的基础科学研究和培训。此外，将基础科学团体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生物医学研究的这两个重要方面做出了重大贡献。智利大学生物系是智利首屈一指的生物系之一。该项目的毕业生对疾病分子基础的研究做出了重大贡献，该系的教师承担或合作开展了疾病分子基础的项目。该项目将向 Bacigalupo 实验室介绍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，但在智利才刚刚开始开发。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，但该国其他地方在基因靶向小鼠的产生方面几乎没有开展工作。这笔赠款的授予将用于培训一名有才华的研究生，以培育基因靶向小鼠。此外，Restrepo 博士还将在智利大学举办为期一周的课程，介绍如何使用基因靶向小鼠进行神经疾病研究。由于两个小组都对基因靶向小鼠感兴趣，我们预计 CECS 和 Bacigalupo 实验室之间未来会有互动。事实上，由于对神经生物学不同方面的共同兴趣，两个群体之间已经存在密切的联系。因此，该FIRCA项目将加强基础科学研究和培训，从而为智利的研究能力建设做出重大贡献。对于疾病研究发展的另一个重要方面是基础研究和临床研究之间形成紧密的联系。此 FIRCA 申请的合格补助金是 NIMH 资助的 Conte 中心补助金，专注于精神分裂症研究（请参阅具体目标）。总体假设是，由于 alfa7 受体启动子多态性导致精神分裂症患者大脑中 alfa7 烟碱乙酰胆碱受体水平降低，这是导致该疾病某些内表型的原因。 Conte 中心的资助涵盖了 DMBXA（一种 alfa7 受体的部分激动剂）从基础研究到 I 期试验的研究。 Restrepo 博士的项目研究嗅觉能力的变化（精神分裂症的内表型）以及多模式相互作用的问题，这些问题导致精神分裂症患者注意力下降和目标导向任务的表现下降。本研究使用基因靶向小鼠，嗅觉作为研究的感觉系统，因为小鼠使用该系统进行交流（通过信息素和其他挥发性化学物质）。其他雷斯特雷波资助的研究重点关注嗅觉的更基本方面，已经产生了重要的见解，我们已经能够将其应用于精神分裂症内表型的研究。从我们发表的工作和其他初步实验表明，直到出生后第 15 天，OSN 中才出现 TRPM5 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，因此我们预计 FIRCA 拨款也将产生与合格拨款相关的信息。重要的是，博士。 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疾病导向研究联系起来。它们都是“Proyecto de Anillos”补充赠款申请的一部分，已发送给 FONDECYT（智利科学技术资助机构）进行评估，由瓦尔帕莱索大学的 Adrian Palacios 博士担任项目主任。该项目的重点是利用八齿鼠研究阿尔茨海默病，八齿鼠是一种啮齿动物，其衰老表型与阿尔茨海默病惊人相似。嗅觉能力下降是阿尔茨海默病的一个标志，由于嗅觉系统在最初的处理阶段相对简单，因此该系统可用于研究该疾病的病理学。我们希望 FIRCA 拨款申请中的工作能够提供与“Proyecto de Anillos”相关的信息。因此，FIRCA 申请将有助于美国和智利基础科学和临床研究之间的联系。