Reduced Motoneuron Excitability in Sepsis

描述（由申请人提供）：虚弱是危重病的一种主要并发症，会使疾病后最初几周的恢复以及疾病后1至2年的生活质量变得复杂。在急性恢复期，虚弱通常会阻止患者脱离呼吸机，延长重症监护室的停留时间，并导致成本、并发症发生率和死亡率大幅增加。在最近发表的一篇论文中，我们发现，在患者和大鼠中，运动神经元难以招募到火是危重疾病引发的虚弱的重要原因。这项研究提供的初步数据表明，在从危重病中恢复后，难以招募运动神经元进行放电， 这可能会导致长期的疲软。运动神经元兴奋性降低作为虚弱的机制从未被提出，因此代表了危重疾病引发虚弱的新研究领域。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结合使用，以确定兴奋性降低的潜在机制。将使用体内运动神经元的动态钳来进一步探索潜在的机制，以纠正导致兴奋性降低的离子通道中的缺陷。初步数据表明，我们已经确定了一种o类药物，可以纠正兴奋性的缺陷。我们希望， 运动神经元兴奋性的改善将迅速转化为新的治疗方法，从而提高患者出院后的康复率和生活质量。

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.