Noradrenergic mechanisms in breathing and respiratory pathophysiologies

呼吸和呼吸病理生理学中的去甲肾上腺素能机制

• 批准号: 10311787
• 负责人: Russell S Ray
• 金额: $ 6.16万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-10 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10311787
• 关键词: Adult; Area; Brain Stem; Breathing; Data; Development; Disease; Embryo; Etiology; Failure; Female; Functional disorder; Glutamates; Grant; Homeostasis; Infant; Laboratories; Life; Measurement; Modeling; Molecular; Mus; Neurodevelopmental Disorder; Neurons; Neurotransmitters; Outcome; Pattern; Play; Production; Reflex action; Research; Respiration Disorders; Respiratory physiology; Resuscitation; Rett Syndrome; Role; Signal Transduction; Sudden infant death syndrome; System; Techniques; United States; Work; congenital respiratory disorder; developmental genetics; hindbrain; innovation; insight; mortality; neonate; neural circuit; noradrenergic; novel; respiratory; respiratory reflex; tool

PROJECT SUMMARY / ABSTRACT This renewal focuses on extending the novel findings developed in the current grant to delineate underlying circuit and molecular mechanisms in noradrenergic (NA) respiratory function and to determine how NA dysfunction may play a role in two life threatening pathophysiologies, Rett Syndrome and Sudden Infant Death Syndrome (SIDS). Rett Syndrome is the leading neuro-developmental disorder in females, presents with severe breathing perturbations, and is associated with NA abnormalities. SIDS is the leading cause of neonate mortality in the United States, claiming 7-14 infants each day and has been associated with NA abnormalities or other circuits that interact with the central NA system. To gain additional insight into NA mechanisms in each of these pathophysiologies, we have developed several intersectional and chemogenetic neural circuit mapping tools that have allowed us to subdivide the NA system into subpopulations defined by their developmental origin for functional assessment in the adult mouse. With these circuit mapping tools and technical enhancements from our laboratory in respiratory measurement techniques, we have found that NA neurons derived from hindbrain rhombomeres 3 and 5 (transient genetically defined segments that embryonically pattern the hindbrain and resulting brainstem; r3,5) give rise to NA sub-types that when chemogenetically silenced, reduce the hypercapnic reflex and when chemogenetically stimulated, enhance the hypercapnic reflex. Leveraging these findings and technical innovations, we have launched three novel areas of research in the NA system. 1) What are the molecular mechanisms in NA system efferent signaling that are important in the hypercapnic reflex? A significant number of r3,5 neurons co-express the neurotransmitter glutamate. Additionally, preliminary data indicates that removing NA production from only r3,5 NA neurons does not affect the hypercapnic reflex, suggesting another transmitter, such as co-expressed glutamate plays a role or can compensate. 2) What role do rhombomere 3,5 NA neurons play in Rett disordered breathing. Our preliminary data suggests that chemogenetic stimulation of r3,5 NA neurons in a mouse Rett model enhances an otherwise nearly absent hypercapnic reflex, indicating that these neurons are still able to drive or modulate chemosensory function in a disease background. 3) What role does the NA system play in the protective neonate auto-resuscitation reflex? Failure of the neonate auto-resuscitation reflex is thought to be a common endpoint for many SIDS cases. We hypothesized that NA chemogenetic stimulation would enhance neonate (P8) auto-resuscitation after a SIDS like challenge. However, we found that stimulation resulted in a near 50% increase in mortality while NA system inhibition appears to enhance survival by 50%. In the proposed work, we seek to determine the molecular and circuit organization of key NA subpopulations in breathing as well as two important respiratory pathophysiologies, SIDS and Rett Syndrome. The outcomes of our work will yield important clues as to how the developmental genetic organization of the central NA system underlies its functional and mechanistic integration into the central respiratory network and how this system may be disrupted to play a role in the etiology of two prevalent developmental respiratory disorders, Rett Syndrome and the fatal Sudden Infant Death Syndrome.

项目概要/摘要 此次更新的重点是扩展当前拨款中开发的新颖发现，以描绘基础电路和 去甲肾上腺素能 (NA) 呼吸功能的分子机制并确定 NA 功能障碍如何发挥作用 两种危及生命的病理生理学，雷特综合症和婴儿猝死综合症（SIDS）。雷特综合症是 女性主要的神经发育障碍，表现为严重的呼吸紊乱，并与 不适用异常。 SIDS 是美国新生儿死亡的主要原因，每天夺走 7-14 名婴儿的生命 与 NA 异常或其他与中枢 NA 系统相互作用的回路有关。为了获得额外的 为了深入了解每种病理生理学中的 NA 机制，我们开发了几种交叉和 化学遗传学神经回路绘图工具使我们能够将 NA 系统细分为定义的亚群 通过其发育起源对成年小鼠进行功能评估。有了这些电路测绘工具和技术 我们实验室在呼吸测量技术方面的改进，我们发现 NA 神经元源自 后脑菱形核 3 和 5（瞬时基因定义的片段，在胚胎模式中形成后脑和 由此产生的脑干； r3,5) 产生 NA 亚型，当化学遗传学沉默时，会降低高碳酸血症反射 当化学遗传学刺激时，增强高碳酸血症反射。利用这些发现和技术 为了创新，我们在 NA 系统中启动了三个新的研究领域。 1）分子机制是什么 NA 系统传出信号对高碳酸血症反射很重要？大量的 r3,5 神经元 共同表达神经递质谷氨酸。此外，初步数据表明，仅从 r3,5 NA 神经元不影响高碳酸反射，表明存在另一种递质，例如共表达的谷氨酸 起到一定作用或者可以起到补偿作用。 2)菱形3,5 NA神经元在Rett呼吸障碍中发挥什么作用。 我们的初步数据表明，在小鼠 Rett 模型中对 r3,5 NA 神经元进行化学遗传学刺激可增强 否则几乎不存在高碳酸反射，表明这些神经元仍然能够驱动或调节化学感应 疾病背景下的功能。 3）NA系统在新生儿保护性自动复苏中发挥什么作用 反射？新生儿自动复苏反射失败被认为是许多 SIDS 病例的常见终点。我们 假设 NA 化学遗传学刺激会增强新生儿 (P8) 在 SIDS 后的自动复苏 挑战。然而，我们发现刺激导致死亡率增加近 50%，而 NA 系统抑制 似乎可以将生存率提高 50%。在拟议的工作中，我们寻求确定分子和电路组织 呼吸中关键的 NA 亚群以及两种重要的呼吸病理生理学：SIDS 和 Rett 综合征。 我们的工作成果将为了解中央 NA 的发育遗传组织如何提供重要线索。 系统是其功能和机械整合到中枢呼吸网络的基础，以及该系统如何可能 被破坏在两种流行的发育性呼吸系统疾病（Rett 综合征和 致命的婴儿猝死综合症。