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.

项目概要/摘要 候选人：沃尔曼博士的职业目标是建立一个独立的研究项目，调查 尼古丁戒断对氧传感的影响已经研究和职业发展计划。 精心设计，为沃尔曼博士提供必要的技能，以建立一个新颖的、独立的产品线 研究并包括以下目标：1）获得研究方法方面的进一步专业知识和 技术，2) 培养教学和指导技能，3) 培养资助写作和进一步学术技能 环境：主要导师 Fregosi 博士是体内研究的专家。 和体外实验，并将为 K99 阶段的 Aim 1 实验提供技术指导。 普拉巴卡尔是颈动脉窦神经记录和颈动脉体球细胞膜片钳方面的专家， Oweiss 博士是体内 gCaMP 成像专家，并将在研究期间为 Wollman 博士提供广泛的培训 K99 阶段。两位导师以及顾问委员会的其他成员将帮助确保 Dr. 沃尔曼的这项建议取得了成功，除了在芝加哥与普拉巴卡博士进行的实践培训。 和佛罗里达州的 Oweiss 一样，这里提出的所有工作都将在 Fregosi 博士的实验室中进行。 在研究项目的培训阶段支持沃尔曼博士所需的 NIH 资金和资源。 亚利桑那大学医学院是该提案指导阶段的理想场所，因为 优秀的教师导师和可用的设施 研究：我的首要假设是尼古丁。 戒断会改变颈动脉体和孤束核（NTS）中的神经元，这是影响神经功能的关键神经结构。 初步数据显示，长期接触尼古丁对氧感应没有影响。 对缺氧的通气反应，然而，在尼古丁 48 小时后，大鼠对缺氧的反应减弱 为了建立在这些新颖的初步数据的基础上，我设计了以下具体目标： 测试尼古丁戒断对 10%、12% 或 15% 缺氧的通气反应的影响，并测试能力 目的 2：测试尼古丁戒断对氧气的影响。 颈动脉体的传感、NTS 神经元的激活以及膈神经的呼吸运动输出 目标 3：测试尼古丁戒断对颈动脉体烟碱乙酰胆碱受体功能的影响。 这项工作将使用体积描记法进行，这是一种独特的体外研究。 使用光纤光度测定法结合体内钙成像和并发膈神经记录，以及 切除的颈动脉体中的血管球细胞和脑干切片中的 NTS 神经元的全细胞膜片钳。 拟议的培训计划将使沃尔曼博士能够学习新的实验技术，成功完成 提议进行研究并过渡到独立的、由外部资助的顶级终身教授职位（R1） 研究机构。