Reduced Motoneuron Excitability in Sepsis

脓毒症时运动神经元兴奋性降低

基本信息

批准号：
9309088
负责人：
MARK M RICH
金额：
$ 32.57万
依托单位：
WRIGHT STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9309088
关键词：
Acute Adult Agonist Area Body Weight decreased Chronic Clinical Research Closure by clamp Complication Critical Illness Data Defect FDA approved Fire - disasters Functional disorder Generations Grant Hospitals Individual Injection of therapeutic agent Intensive Care Units Ion Channel Maintenance Mechanical ventilation Membrane Potentials Modeling Motor Motor Neurons Muscle Nerve Neuraxis Paper Patients Peripheral Peripheral Nerves Pharmaceutical Preparations Phase Physiologic pulse Play Process Publishing Quality of life Quipazine Ramp Rattus Recovery Recruitment Activity Rehabilitation therapy Reporting Research Riluzole Role Secondary to Sepsis Serotonin Agonists Techniques Testing Time Translating Ventilator Weaning Work cost disability drug testing improved improved outcome in vivo mortality neuromuscular transmission neuronal cell body novel novel therapeutics prevent public health relevance response septic systemic toxicity therapy development

项目摘要

DESCRIPTION (provided by applicant): Weakness is a major complication of critical illness that complicates recovery both during the first few weeks following illness as well as the quality of life 1 to 2 years after the illness. During the acute recovery period, weakness often prevents patient weaning from the ventilator, prolonging intensive care unit stays, and leading to greatly increased cost, complication rates and mortality. In a recently published paper we found, in both patients and rats, that difficulty in recruitment of motoneurons to fire is an important contributo to weakness triggered by critical illness. Preliminary data presented in this grant suggests difficulty recruiting motoneurons to fire may persist after recovery from critical illness and thus may contribute to long term weakness. Reduced motoneuron excitability as a mechanism of weakness has never been proposed and thus represents a novel area of research into weakness triggered by critical illness. In vivo intracellular recording from motoneurons in adult rats will be used in combination with modeling of motoneuron excitability to identify potential mechanisms underlying the reduction of excitability. Potential mechanisms will further be explored using dynamic clamp of motoneurons in vivo to correct the defect(s) in ion channels that underlie the reduction in excitability. Preliminary data suggests we have identified a class o drugs that can correct the defect in excitability. It is our hope that identification of drugs that improve motoneuron excitability will rapidly translate to new therapy that improves the rate of rehabilitation and the quality of life for patients after hospital discharge.

描述（由申请人提供）：弱点是危重疾病的主要并发症，在疾病后的头几周以及生命后的1至2年生活质量使康复变得复杂。在急性恢复期间，弱点通常会阻止患者从呼吸机中断奶，延长重症监护病房，并导致成本，并发症率和死亡率大大提高。在最近发表的论文中，我们发现，在患者和大鼠中，招募运动神经元的难度是危害疾病引发的弱点的重要贡献。这笔赠款中提供的初步数据表明，在恢复重症病后，难以招募运动神经元可能会持续存在，从而持续可能会导致长期弱点。从未提出过降低的运动神经元兴奋性作为无力的机制，因此代表了严重疾病引发的无力研究的新型研究领域。成年大鼠运动神经元的体内细胞内记录将与运动神经元兴奋性建模相结合，以鉴定降低兴奋性的潜在机制。将使用体内运动神经元的动态夹进一步探索潜在的机制，以纠正降低兴奋性的离子通道中的缺陷。初步数据表明，我们已经确定了可以在兴奋性中纠正缺陷的类O类药物。我们希望识别药物改善运动神经元的兴奋性将迅速转化为新疗法，从而提高了出院后患者的康复率和生活质量。