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.

项目总结/摘要 尽管肥胖换气不足综合征（OHS）影响每220名美国人中就有1人的健康， 目前的治疗缺乏有效性或依从性差。新疗法的发展 由于该领域几乎只关注个人的身体力学或代谢率， 肥胖相关呼吸道病理生理学的主要原因。我们的长期目标是确定新的 可以有效治疗肥胖相关呼吸道疾病的策略。本建议的总体目标是 来定义将代谢神经生物学与化疗敏感性降低联系起来的回路。我们的中央 下丘脑对中脑导水管周围灰质（PAG）的调节导致肥胖的假说- 相关的化疗敏感性降低。其基本原理是，通过定义连接肥胖诱导的 下丘脑的变化，以减少化学敏感性，这一建议的结果可能会促进 开发旨在对抗职业健康安全的新药物治疗。核心假设是 在以下具体目标中进行测试： 目标1.确定调节PAG的下丘脑群体。使用转基因的 小鼠模型，免疫组织化学和病毒示踪，这一目标确定下丘脑脑区， 通过中脑PAG参与化学敏感性调节的信号机制 目标2.确定最大程度影响体内化疗敏感性的神经元靶点。使用化学 技术和全身体积描记术，这一目标决定了我们的每个候选人 区域在肥胖的情况下调节呼吸。 这一提议有望定义一种新的神经生物学回路，肥胖通过该回路影响化疗敏感性。这 这项提案是创新的，因为它超越了普遍认为的肥胖相关呼吸道疾病 主要是身体力学的结果，而是确定了调节神经元的关键神经元群体。 体内化疗敏感性。预计这一贡献将大大提高外地对 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 开发新的，更有效的治疗肥胖相关的呼吸系统疾病，针对潜在的 神经病理生理学