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

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 尽管肥胖低呼吸综合征(OHS)影响着每220个美国人中就有一个人的健康， 目前的治疗方法缺乏有效性或依从性较差。新疗法的开发已经被 受阻于该领域对个人身体机能或代谢率的近乎专一的关注 与肥胖相关的呼吸道病理生理学的主要原因。我们的长期目标是发现新的 能够有效治疗肥胖相关呼吸系统疾病的策略。这项提议的总体目标是 以确定代谢神经生物学与降低化疗敏感性之间的联系。我们的中央 假设是下丘脑对中脑导水管周围灰质(PAG)的调节导致肥胖- 化疗敏感性的相关降低。其基本原理是，通过定义与肥胖诱导有关的回路 下丘脑的变化降低了对化疗的敏感性，这一提议的结果可能会促进 旨在对抗OHS的新药物治疗方法的开发。中心假设将是 在以下具体目标中进行了测试： 目的1.确定调节PAG的下丘脑群。使用转基因的组合 小鼠模型、免疫组织化学和病毒追踪，目的是识别下丘脑区域和 中脑PAG参与化疗敏感性调节的信号机制 目的2.确定对体内化疗敏感性影响最大的神经元靶点。使用化学诱导剂 技术和全身体积描记术，这一目标决定了我们每个候选人 在肥胖的背景下，区域调节呼吸。 这项提议有望定义肥胖影响化疗敏感性的一种新的神经生物学回路。这 这项提案是创新的，因为它超越了人们普遍持有的与肥胖相关的呼吸道疾病的观点 主要是身体物理力学的结果，而不是识别调节 体内化疗敏感性。这一贡献预计将大大增加该领域对 肥胖相关的呼吸道病理生理学。最终，我们相信这一贡献将催化 开发针对肥胖相关呼吸系统疾病的新的、更有效的治疗方法 神经病理生理学。