Proposed roles of KCNQ2 Channels in Respiratory Homeostasis

KCNQ2 通道在呼吸稳态中的拟议作用

• 批准号: 10544558
• 负责人: Jaseph Soto
• 金额: $ 4.35万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-07 至 2025-01-06
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544558
• 关键词: Affect; Animals; Apnea; Behavior; Brain; Breathing; Carbon Dioxide; Cell Nucleus; Chemoreceptors; Chronic; Clinical; Clinical Data; Clinical Research; Disease; Electrophysiology (science); Elements; Encephalopathies; Exhibits; Foundations; Functional disorder; Generations; Genes; Goals; Homeostasis; Hypoventilation; Impairment; Lead; Modeling; Molecular; Motor Neurons; Motor output; Mus; Mutation; Neonatal; Neurons; Neurotransmitters; Nucleus solitarius; Output; Pathogenicity; Patients; Pharmacology; Phenotype; Positioning Attribute; Potassium Channel; Rattus; Recurrence; Research; Research Personnel; Respiration Disorders; Respiratory Disease; Role; Slice; Symptoms; Syndrome; System; Testing; Training; Transgenic Mice; Variant; Work; cell type; congenital central hypoventilation syndrome; epileptic encephalopathies; gain of function; gain of function mutation; infancy; insight; loss of function; loss of function mutation; mouse model; neonatal brain; novel; preBotzinger complex; profiles in patients; respiratory; response; therapeutic target; therapy development

PROJECT SUMMARY/ABSTRACT KCNQ channels are key determinants of neuronal activity, and recent clinical evidence identifies mutations in KCNQ2 as a cause of neonatal epileptic encephalopathy. Most variants associated with neonatal epileptic encephalopathy are Loss-of-Function.However, recent work also identified a recurrent KCNQ2 Gain-of-Function mutation (R201C) in patients with neonatal onset encephalopathy. Patients with both KCNQ2 Loss- and Gain- of-Function mutations exhibit respiratory dysfunction including central hypoventilation syndrome, a condition thought to result from loss of respiratory chemoreception, i.e., the mechanism by which the brain regulates breathing in response to CO2/H+. The retrotrapezoid nucleus (RTN) is an important chemoreceptor region, and we have shown previously that KCNQ channels regulate basal activity and neurotransmitter modulation of RTN chemoreceptors. Therefore, I hypothesize that KCNQ2 channels are the principal KCNQ subunits that control activity of RTN chemoreceptors. Ipropose that KNCQ2 Gain-of-Functionwill hyperpolarize RTNchemoreceptors and eliminate their contribution to the drive to breathe, whereas KCNQ2 Loss-of-Function mutations will destabilize RTN chemoreceptor activity and disrupt modulation by neurotransmitters, thus also contributing to unstable breathing. Additionally, I will also test whether KCNQ2 dysfunction affects not only the RTN but the respiratory control circuit in general including other chemoreceptors, inspiratory rhythmogenic pre-Bötzinger complex neurons, and output respiratory motor neurons. Objectives of this study are to investigate, from the cellular to system level, contributions of KCNQ2 channels to chemoreceptorfunction and respiratory control. The two Specific Aims of this project are: 1) determine cellular effects of KCNQ2 on respiratory chemoreception, inspiratory rhythmgeneration and motor output and 2) determine the essential role of KCNQ2 channels in control of breathing. The rationale for the proposed research is that by understandingwhether and howKCNQ2 channels regulate neuronal activity across multiple levels of the respiratory circuit, and respiratory behavior, I will lay a foundation for development of treatments for respiratory problems like apnea and central hypoventilation syndrome.

项目总结/摘要 KCNQ通道是神经元活动的关键决定因素，最近的临床证据表明， KCNQ 2是新生儿癫痫性脑病的病因与新生儿癫痫相关的大多数变异 然而，最近的研究也发现了一种复发性KCNQ 2功能获得性 突变（R201 C）在新生儿发病性脑病患者。KCNQ 2丢失和获得的患者 功能突变表现出呼吸功能障碍，包括中枢性低通气综合征， 被认为是由于呼吸化学感受的丧失，即，大脑调节的机制 呼吸响应CO2/H+。后斜方核（RTN）是一个重要的化学感受器区域， 我们以前已经证明KCNQ通道调节RTN的基础活动和神经递质调节 化学感受器因此，我假设KCNQ 2通道是控制KCNQ亚基的主要KCNQ亚基。 RTN化学感受器的活性。我认为KNCQ 2功能获得将增加RTN化学受体 并消除它们对呼吸驱动的贡献，而KCNQ 2功能丧失突变将 使RTN化学感受器活性不稳定并破坏神经递质的调节，因此也有助于 呼吸不稳此外，我还将测试KCNQ 2功能障碍是否不仅影响RTN， 呼吸控制回路一般包括其他化学感受器，吸气节律性前Bötzinger 复杂神经元和输出呼吸运动神经元。本研究的目的是调查，从 细胞到系统水平，KCNQ 2通道对化学感受器功能和呼吸控制的贡献。的 该项目的两个具体目的是：1）确定KCNQ 2对呼吸化学感受的细胞效应， 吸气节律的产生和运动输出; 2）确定KCNQ 2通道在控制中的重要作用 呼吸。该研究的基本原理是，通过了解KCNQ 2通道是否以及如何 调节呼吸回路多个层次的神经元活动和呼吸行为，我将奠定一个 呼吸暂停和中枢性换气不足等呼吸问题治疗发展基金会 综合征