The Influence of Nicotine Withdrawal on Oxygen Sensing

尼古丁戒断对氧感应的影响

• 批准号: 10505964
• 负责人: Lila B Wollman
• 金额: $ 13.31万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10505964
• 关键词: Acute; Adult; Advisory Committees; Arizona; Blood gas; Brain Stem; Breathing; Calcium; Carotid Body; Cell Nucleus; Cells; Chemicals; Chicago; Chronic; Clinical; Data; Development Plans; Dose; Educational process of instructing; Electrophysiology (science); Ensure; Equilibrium; Extramural Activities; Fiber; Florida; Fluorescent Dyes; Funding; Glomus Cell; Glutamates; Grant; Health; Hour; Human; Hypoxia; Image; Impairment; In Vitro; Injections; Institution; Intravenous; Laboratories; Leadership; Learning; Letters; Lung; Mammals; Measures; Mechanical ventilation; Mediating; Medicine; Mentors; Motor; Motor Activity; Motor output; Nerve; Neurons; Nicotine; Nicotine Withdrawal; Nicotinic Receptors; Operative Surgical Procedures; Oxygen; Pathway interactions; Patients; Phase; Photometry; Plethysmography; Positioning Attribute; Preparation; Rattus; Receptor Activation; Reflex action; Research; Research Methodology; Research Project Grants; Research Technics; Resources; Rest; Sensory; Severities; Site; Slice; Smoker; Smoking; Structure; Structure of phrenic nerve; Techniques; Testing; Time; Tobacco smoke; Training; Travel; United States National Institutes of Health; Universities; Withdrawal Symptom; Work; Writing; awake; calcium indicator; career; career development; carotid sinus; college; design; experimental study; faculty mentor; in vivo; in vivo calcium imaging; medical complication; metabolic rate; nicotine exposure; nicotine use; novel; patch clamp; programs; receptor function; receptor upregulation; relating to nervous system; research and development; respiratory; response; skills; success; tenure track

PROJECT SUMMARY/ABSTRACT CANDIDATE: Dr. Wollman’s career objective is to establish an independent research program investigating the influence of nicotine withdrawal on oxygen sensing. The research and career development plans have been carefully designed to provide the necessary skills for Dr. Wollman to establish a novel, independent line of research and include the following objectives: 1) to gain further expertise in research methodology and techniques, 2) develop teaching and mentoring skills, and 3) to develop grant writing skills and further academic leadership skills. ENVIRONMENT: Primary mentor Dr. Fregosi is an expert in studying breathing both in vivo and in vitro and will provide technical guidance for Aim 1 experiments during the K99 phase. Mentors Dr. Prabhakar is an expert in carotid sinus nerve recordings and patch clamp from carotid body glomus cells, and Dr. Oweiss is an expert in vivo gCaMP imaging, and will provide extensive training to Dr. Wollman during the K99 phase. Both mentors, along with the rest of the assembled advisory committee, will help to ensure Dr. Wollman’s success with this proposal. With the exception of hands on training with Drs. Prabhakar in Chicago and Oweiss in Florida, all of the work proposed here will be carried out in the Fregosi laboratory. Dr. Fregosi has NIH funding and the resources needed to support Dr. Wollman during the training phase of the research project. The University of Arizona College of Medicine is an ideal setting for the mentored phase of this proposal due to the outstanding faculty mentors and facilities available. RESEARCH: My overarching hypothesis is that nicotine withdrawal alters the carotid body and neurons in the nucleus tractus solitarius (NTS), key neural structures that are involved in oxygen sensing. Preliminary data shows that chronic nicotine exposure has no effect on the ventilatory response to hypoxia, however rats show a blunted response to hypoxia after 48 hours of nicotine withdrawal. To build on these novel preliminary data, I have designed the following specific aims. Aim 1: To test the effects of nicotine withdrawal on the ventilatory response to 10, 12, or 15% hypoxia, and to test the ability for an acute dose of nicotine to rescue this response. Aim 2: To test the effects of nicotine withdrawal on oxygen sensing in the carotid body, NTS neuron activation and the respiratory motor output from the phrenic nerve in vivo. Aim 3: To test the effects of nicotine withdrawal on nicotinic acetylcholine receptor function in carotid body glomus cells and NTS neurons in vitro. This work will be carried out using plethysmography, a unique combination of in vivo calcium imaging using fiber photometry, and concurrent phrenic nerve recordings, and whole cell patch clamp of glomus cells in excised carotid bodies and NTS neurons in a brainstem slice. The proposed training plan will allow Dr. Wollman to learn new experimental techniques, successfully complete the proposed research and transition to an independent, extramurally-funded tenure-track position at a top-tier (R1) research institution.

项目摘要/摘要 候选人：沃尔曼博士的职业目标是建立一个独立研究计划，以调查 尼古丁戒断对氧气感应的影响。研究和职业发展计划已经 精心设计的旨在为沃尔曼博士提供必要的技能，以建立一条新颖，独立的行 研究并包括以下目标：1）在研究方法论方面获得进一步的专业知识 技术，2）发展教学和心理技能，3）发展授予写作技巧和进一步的学术 领导技能。环境：主要导师Fregosi博士是研究呼吸的专家 并在体外，将在K99阶段为AIM 1实验提供技术指导。导师博士 Prabhakar是颈动脉窦神经记录和颈动脉体glomus细胞的斑块夹的专家， Oweiss博士是体内GCAMP成像专家 K99阶段。两位导师以及集会咨询委员会的其余成员都将有助于确保博士 沃尔曼（Wollman）在此提案中取得了成功。除了与Drs进行培训外。芝加哥的Prabhakar 在佛罗里达州的Oweiss，这里提出的所有工作将在Fregosi实验室进行。 Fregosi博士有 在研究项目的培训阶段，NIH资金和支持沃尔曼博士所需的资源。 亚利桑那大学医学院是由于 杰出的教师导师和设施可用。研究：我的总体假设是尼古丁 戒断会改变颈动脉体和神经元的核曲纳氏菌（NTS），关键神经元结构 参与氧气感应。初步数据表明，慢性尼古丁暴露对 对缺氧的通气反应，但是48小时后，大鼠对缺氧的反应钝化 提取。为了基于这些新颖的初步数据，我设计了以下特定目标。目标1：到 测试尼古丁提取对10％，12％或15％缺氧的通风反应的影响，并测试能力 为了急性剂量的尼古丁来营救这种反应。目标2：测试尼古丁戒断对氧气的影响 在颈动脉体内感测NTS神经元激活和phrenic神经的呼吸运动输出 体内。目标3：测试尼古丁戒断对颈动脉体内烟碱乙酰胆碱受体功能的影响 肾小球细胞和NTS神经元体外。这项工作将使用Plethysmography进行，这是一个独特的 使用纤维光度法和并发的神经记录的体内钙成像组合，以及 脑干切片中出色的颈动脉体和NTS神经元中肾小球细胞的全细胞斑块夹。这 拟议的培训计划将使沃尔曼博士能够学习新的实验技术，并成功完成 拟议的研究和过渡向独立的，外部资助的终身轨道位置（R1） 研究机构。