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.

项目概要/摘要 尽管肥胖通气不足综合症 (OHS) 影响着每 220 名美国人中就有 1 人的健康， 目前的治疗方法缺乏有效性或依从性差。新治疗方法的开发一直在进行。 该领域几乎只关注个人的身体力学或新陈代谢率，这阻碍了这一领域的发展 我们的长期目标是找到新的导致肥胖相关呼吸病理生理学的主要原因。 该提案的总体目标是有效治疗肥胖相关呼吸道疾病的策略。 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。 假设是下丘脑对中脑导水管周围灰质（PAG）的调节导致肥胖 其原理是通过定义与肥胖相关的电路来降低化疗敏感性。 下丘脑的变化导致化疗敏感性降低，该提案的结果可能会促进 开发旨在对抗 OHS 的新药物治疗方法的中心假设是。 测试的具体目标如下： 目标 1. 使用转基因组合鉴定调节 PAG 的下丘脑群体。 小鼠模型、免疫组织化学和病毒追踪，这一目标确定了下丘脑大脑区域和 通过中脑 PAG 调节化疗敏感性的信号传导机制 目标 2. 使用化学原性确定对化疗体内敏感性影响最大的神经靶点。 技术和全身体积描记法，这个目标决定了我们每个候选人的程度 区域在肥胖的情况下调节呼吸。 该提案预计将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。 该提案具有创新性，因为它超越了肥胖相关呼吸道疾病这一普遍观点 主要是由身体力学产生的，而是识别调节的关键神经群 这一贡献预计将显着增加该领域对体内化学敏感性的理解。 最终，我们相信这一贡献将促进肥胖相关的呼吸病理生理学的发展。 针对肥胖相关呼吸系统疾病开发新的、更有效的治疗方法 神经病理生理学。