Reduced Motoneuron Excitability in Sepsis

描述(由申请人提供)：虚弱是危重疾病的一个主要并发症，它使疾病后最初几周的康复以及疾病后1至2年的生活质量变得复杂。在急性恢复期，虚弱往往会阻止患者脱离呼吸机，延长重症监护病房的停留时间，并导致成本、并发症发生率和死亡率的大幅增加。在最近发表的一篇论文中，我们在患者和大鼠身上都发现，运动神经元难以招募到火是导致危重疾病引发的虚弱的重要原因。这项赠款中提供的初步数据表明，在危重疾病恢复后，难以招募运动神经元进行点火可能会持续下去，因此 可能会导致长期的疲软。运动神经元兴奋性降低作为一种虚弱的机制从未被提出，因此代表了一个由危重疾病引发的虚弱的新研究领域。成年大鼠运动神经元的活体细胞内记录将与运动神经元兴奋性的建模相结合，以确定兴奋性降低的潜在机制。可能的机制将进一步探索利用体内运动神经元的动态钳制来纠正离子通道中的缺陷(S)，这是兴奋性降低的基础。初步数据显示，我们已经确定了一类可以纠正兴奋性缺陷的O类药物。我们希望对毒品的鉴定 改善运动神经元的兴奋性将迅速转化为新的治疗方法，提高患者出院后的康复速度和生活质量。

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.