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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.

项目摘要/摘要