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Interactions of the Noradrenergic and Serotonergic Systems in Autoresuscitation

去甲肾上腺素能系统和血清素能系统在自动复苏中的相互作用

基本信息

批准号：
10812310
负责人：
Savannah J Lusk
金额：
$ 7.63万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2025-09-14
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10812310
关键词：
Anoxia Autopsy Biological Assay Brain Stem Breathing Breeding Cause of Death Cells Cessation of life Clozapine Compensation Data Development Diagnostic Disease Educational workshop Environment Equipment Failure Foundations Functional disorder Future Genetic Health Homeostasis Immunohistochemistry Infant Investigation Joints Knowledge Lesion Life Link Medical History Methodology Methods Mus Outcome Oxides Phenotype Population Reflex action Regulation Research Resolution Respiration Disorders Respiratory Center Respiratory System Role Serotonergic System Serotonin Solid Stains Sudden infant death syndrome Symptoms System Technology Testing Therapeutic Therapeutic Intervention Tissues Toxin Training United States Work combinatorial congenital respiratory disorder course development disease diagnosis genetic manipulation infant death loss of function mortality neonate neural network neuroregulation noradrenergic novel pharmacologic protective effect recombinase respiratory respiratory challenge respiratory reflex response tool

项目摘要

Project Summary/ Abstract The noradrenergic (NA) and serotonergic (5-HT) networks of the brainstem are highly regulated and necessary components of the respiratory homeostatic network. Dysfunction of these systems has been linked to many congenital respiratory disorders including Sudden Infant Death Syndrome (SIDS). SIDS is a leading cause of neonate death and is thought to occur, in part, by the failure of the neonate autoresuscitation reflex. Previous data have informed our understanding of how these systems modulate protective respiratory responses to life threatening challenges independently, but limited information is available on the potential interplay between these two key systems while previous studies lack a more finessed manipulation provided by our methodology. In the following aims, I will test the hypothesis that the 5-HT and NA systems are integrally linked in regulating the autoresuscitation reflex and that different combinations of 5-HT and NA perturbation and stimulation will result in additive positive and negative outcomes in autoresuscitation. Aim 1. Determine the separate and combined functional and cellular effects of serotonergic activation and noradrenergic inhibition on the autoresuscitation reflex and respiratory network dynamics in response to hypercapnic anoxia. Aim 2. Determine the effect of serotonergic inhibition and noradrenergic activation on the autoresuscitation reflex. Aim 3. Determine the effect of serotonergic inhibition and noradrenergic inhibition or serotonergic activation and noradrenergic activation on the autoresuscitation reflex. To test these aims, I will utilize compounded recombinase and effector lines to access and manipulate the activity of the 5-HT and NA systems. For example, the Pet1::Cre; F_hM4D line bred to a DBH_FLPo; P_hM3D line will produce mice that, upon clozapine-N-oxide (CNO) application, will concurrently excite the 5-HT system (Pet1::Cre + P_hM3D) while inhibiting the NA system (DBH_FLPo + F_hM4D). For functional characterizations, the mice will be challenged with repeated bouts of hypercapnic anoxia to test their autoresuscitation reflex. For network activity characterization, cFos staining will be carried out on brainstem tissue in mice that have been challenged with sublethal hypercapnic anoxic exposures after excitation or inhibition of the 5-HT or NA systems. Understanding if these systems are independently regulating autoresuscitation will provide valuable information for future therapeutic investigations. This study will progress the field by expanding our understanding of interplay between the 5-HT and NA systems in health and disease as well as informing on the use of intricate genetic manipulations in the study of these two key respiratory systems. This work will significantly advance our understanding of the neural networks involved in respiratory regulation and disease. The training plan and environment that accompany this proposal will provide a solid foundation for a transition to research independence. Training includes scientific and professional development courses, workshops, and seminars while the environment includes cutting edge technology and equipment with training offered in house at BCM.

项目总结/摘要脑干的去甲肾上腺素能（NA）和肾上腺素能（5-HT）网络是高度调节和必需的呼吸稳态网络的组成部分。这些系统的功能失调与许多先天性呼吸系统疾病，包括婴儿猝死综合征（SIDS）。小岛屿发展中国家是造成新生儿死亡，并且被认为部分是由于新生儿自动复苏反射的失败而发生的。先前这些数据使我们了解了这些系统如何调节对生命的保护性呼吸反应独立的威胁挑战，但有限的信息可用于之间的潜在相互作用这两个关键系统，而以前的研究缺乏一个更巧妙的操纵提供了我们的方法。在下面的目的中，我将检验这一假设，即5-HT和NA系统在调节细胞凋亡中是整体联系在一起的。自动复苏反射和5-HT和NA扰动和刺激不同组合将在自动复苏中导致附加的阳性和阴性结果。目标1.确定单独的和肾上腺素能激活和去甲肾上腺素能抑制对肾上腺素能受体的功能和细胞的联合作用。高碳酸性缺氧时的自动复苏反射和呼吸网络动力学。目标2.确定血清素能抑制和去甲肾上腺素能激活对自动复苏反射的影响。目标3. 确定肾上腺素能抑制和去甲肾上腺素能抑制或肾上腺素能激活的作用，去甲肾上腺素能激活的自动复苏反射。为了测试这些目标，我将使用复合重组酶和效应细胞系以接近和操纵5-HT和NA系统的活性。比如说，与DBH_FLPo; P_hM3D品系交配Pet 1：：Cre; F_hM4D品系将产生小鼠，在氯氮平-N-氧化物 (CNO)应用，将同时激发5-HT系统（Pet 1：：Cre + P_hM3D），同时抑制NA系统 (DBH_FLPo + F_hM4D）。对于功能表征，小鼠将用重复发作的高碳酸盐性缺氧，以测试其自动复苏反射。对于网络活性表征，cFos染色将在已经用亚致死高碳酸缺氧激发的小鼠的脑干组织上进行在5-HT或NA系统的激发或抑制后暴露。了解这些系统是否独立调节自体复苏将为未来的治疗研究提供有价值的信息。这项研究将通过扩大我们对5-HT和NA系统之间相互作用的理解来推动这一领域的发展在健康和疾病方面的作用，以及在这两个方面的研究中使用复杂的基因操作的信息关键的呼吸系统这项工作将大大推进我们对所涉及的神经网络的理解在呼吸调节和疾病方面。本建议书附带的培训计划和环境将为向研究独立过渡提供了坚实的基础。培训包括科学和专业开发课程，讲习班和研讨会，而环境包括尖端技术和设备，并在总部提供培训。