Cultivating novel treatments for obesity-related respiratory disease by uncovering neuronal etiology

通过揭示神经元病因来开发治疗肥胖相关呼吸系统疾病的新疗法

• 批准号: 10730653
• 负责人: Deanna Marie Arble
• 金额: $ 45.69万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-05 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730653
• 关键词: Affect; American; Anatomy; Body Weight; Brain region; Breathing; Data; Development; Down-Regulation; Effectiveness; Etiology; Failure; Fostering; Functional disorder; Goals; Health; Hypothalamic structure; Immunohistochemistry; In Vitro; Individual; Link; Literature; Mediating; Melanocortin 4 Receptor; Metabolic; Midbrain structure; Mission; Modeling; Mus; National Heart, Lung, and Blood Institute; Neurobiology; Neurologic; Neurons; Neuropeptides; Obesity; Obstructive Sleep Apnea; Outcome; Pharmacologic Substance; Pickwickian Syndrome; Population; Positioning Attribute; Prevalence; Public Health; Publishing; Regulation; Research; Respiration Disorders; Respiratory Disease; Respiratory Mechanics; Respiratory physiology; Signal Transduction; Structure of nucleus infundibularis hypothalami; Technology; Testing; Thinness; Time; Transgenic Mice; United States National Institutes of Health; Viral; Whole Body Plethysmography; body mechanics; combat; effective therapy; gamma-Aminobutyric Acid; in vivo; innovation; interest; metabolic rate; midbrain central gray substance; mouse model; novel; novel therapeutic intervention; obesity treatment; paraventricular nucleus; prevent; respiratory; therapy design; Affect; American; Anatomy; Body Weight; Brain region; Breathing; Data; Development; Down-Regulation; Effectiveness; Etiology; Failure; Fostering; Functional disorder; Goals; Health; Hypothalamic structure; Immunohistochemistry; In Vitro; Individual; Link; Literature; Mediating; Melanocortin 4 Receptor; Metabolic; Midbrain structure; Mission; Modeling; Mus; National Heart, Lung, and Blood Institute; Neurobiology; Neurologic; Neurons; Neuropeptides; Obesity; Obstructive Sleep Apnea; Outcome; Pharmacologic Substance; Pickwickian Syndrome; Population; Positioning Attribute; Prevalence; Public Health; Publishing; Regulation; Research; Respiration Disorders; Respiratory Disease; Respiratory Mechanics; Respiratory physiology; Signal Transduction; Structure of nucleus infundibularis hypothalami; Technology; Testing; Thinness; Time; Transgenic Mice; United States National Institutes of Health; Viral; Whole Body Plethysmography; body mechanics; combat; effective therapy; gamma-Aminobutyric Acid; in vivo; innovation; interest; metabolic rate; midbrain central gray substance; mouse model; novel; novel therapeutic intervention; obesity treatment; paraventricular nucleus; prevent; respiratory; therapy design

PROJECT SUMMARY / ABSTRACT Despite Obesity Hypoventilation Syndrome (OHS) affecting the health of 1 in every 220 US Americans, current treatments lack effectiveness or have poor compliance. The development of new treatments has been hindered by the field’s near exclusive focus on an individual’s physical body mechanics or metabolic rate as the primary cause of obesity-related respiratory pathophysiology. Our long-term goal is to identify new strategies that can effectively treat obesity-related respiratory diseases. The overall objective of this proposal is to define the circuitry that links metabolic neurobiology to a reduction in chemosensitivity. Our central hypothesis is that hypothalamic modulation of the midbrain periaqueductal gray (PAG) results in obesity- related reductions in chemosensitivity. The rationale is that by defining the circuitry that links obesity-induced hypothalamic changes to reduced chemosensitivity, the outcomes of this proposal are likely to foster the development of new pharmaceutical treatments designed to combat OHS. The central hypothesis will be tested in the following specific aims: Aim 1. Identify the hypothalamic populations that modulate the PAG. Using a combination of transgenic mouse models, immunohistochemistry, and viral tracing, this aim identifies the hypothalamic brain regions and signaling mechanisms involved in the modulation of chemosensitivity via the midbrain PAG Aim 2. Determine the neuronal targets that maximally affect in vivo chemosensitivity. Using chemogenic technology and whole-body plethysmography, this aim determines the extent to which each of our candidate regions modulate breathing in the context of obesity. This proposal is expected to define a novel neurobiological circuit by which obesity affects chemosensitivity. This proposal is innovative because it moves beyond the popularly held view that obesity-related respiratory disease principally results from physical body mechanics, and instead, identifies key neuronal populations that modulate in vivo chemosensitivity. This contribution is expected to significantly increase the field’s understanding of obesity-related respiratory pathophysiology. Ultimately, we believe this contribution will catalyze the development of new, more effective treatments for obesity-related respiratory diseases that target the underlying neuro-pathophysiology.

项目摘要 /摘要 尽管肥胖不足综合征（OHS）影响了每220个美国人中1的健康，但 目前的治疗缺乏效力或依从性不佳。新疗法的发展已经 该领域几乎专注于个人的身体机理或代谢率的限制 与肥胖相关的呼吸病理生理学的主要原因。我们的长期目标是确定新的 可以有效治疗与肥胖有关的呼吸道疾病的策略。该提议的总体目标是 定义将代谢神经生物学与化学敏感性降低联系起来的电路。我们的中心 假设是中脑周围灰色（PAG）的下丘脑调节导致肥胖 化学敏感性的相关降低。理由是通过定义连接肥胖诱导的电路 下丘脑变化以降低化学敏感性，该提案的结果可能会促进 开发旨在对抗OHS的新药物治疗方法。中心假设将是 在以下特定目标中进行了测试： 目标1。确定调节PAG的下丘脑种群。结合转基因 小鼠模型，免疫组织化学和病毒追踪，此目标确定了下丘脑大脑区域和 通过中脑PAG调节化学敏的信号传导机制 AIM 2。确定最大程度地影响体内化学敏感性的神经元靶标。使用化学生成 技术和全身庞大的描绘，此目的决定了我们每个候选人的程度 区域在肥胖症的背景下调节呼吸。 预计该建议将定义一个新的神经生物学回路，肥胖会影响化学敏感性。这 提案具有创新性，因为它超越了与肥胖相关呼吸系统疾病的流行观点 主要是由身体力学产生的，而是确定调节的关键神经元种群 体内化学敏感性。预计这一贡献将大大提高该领域对 与肥胖相关的呼吸病理生理学。最终，我们认为这项贡献将催化 开发针对肥胖相关呼吸道疾病的新的，更有效的治疗方法 神经病理生理学。