Sleep and fatigue during renal disease in mice

描述（由申请人提供）：嗜睡和睡眠质量广泛影响一般健康状况的测量，特别是影响对能量、疲劳和一般健康状况的感知。疲劳和睡眠紊乱也是患有慢性病或接受相关治疗的人的常见和致残问题。特别是，患有肾脏疾病的人经常出现睡眠障碍和严重疲劳，这些都可能独立于透析发生。有趣的数据支持睡眠，免疫功能和感染性或炎症性疾病之间的显着相互作用，但在这些疾病期间疲劳和睡眠紊乱的原因尚不确定。确定在疾病状态下调节睡眠和警惕性的物质和机制，应有助于最终开发可以控制或预防这些衰弱症状的干预措施，从而改善许多人的生活质量。 我们的初步数据表明，近交系小鼠发生急性肾盂肾炎引起的白色念珠菌发展应变依赖性变化的睡眠模式，不同的疾病严重程度。我们的工作模型是，宿主防御反应的变化与疲劳和睡眠紊乱等症状的发展以及疾病的易感性和严重程度有关。我们的长期目标是确定这个复杂的病理生理网络。 为此，我们提出了一个全基因组搜索，以确定一个仍然未知的一组基因，有助于在感染引起的肾脏疾病的行为和/或生理反应的变化。这些研究将提供必要的关键数据，以确定介导睡眠改变的基因，并将这些基因与其他疾病标志物联系起来。目的1将评估小鼠品系在中毒性肾病期间睡眠的差异。目标2和3将扫描基因组以定位调控“热点”。“目标4将通过评估强候选基因的贡献来利用这些发现。鉴于我的实验室在其他涉及大量小鼠的研究中调查睡眠表型的经验，实现这一雄心勃勃的目标是可行的。

DESCRIPTION (provided by applicant): Sleepiness and sleep quality broadly influence measures of general health status, particularly impacting perceptions about energy, fatigue, and general well being. Fatigue and disturbed sleep are also common and disabling problems for persons undergoing chronic diseases or associated therapies. In particular, people with renal disease frequently develop disturbed sleep and severe fatigue that can occur independent of dialysis. Intriguing data support significant interactions between sleep, immune function, and infectious or inflammatory disease, but the cause of fatigue and disturbed sleep during such disorders is uncertain. Identifying substances and mechanisms that modulate sleep and vigilance during disease states should contribute to the eventual development of interventions that can control or prevent these debilitating symptoms and thus improve the quality of life of many people. Our preliminary data indicate that inbred mice undergoing acute pyelonephritis induced by Candida albicans develop strain-dependent variation in patterns of sleep, and varying severity of disease. Our working model is that variation in the host defense response is linked to the development of symptoms such as fatigue and disturbed sleep, and to disease susceptibility and severity. Our long-term goal is to define this complex pathophysiologic network. Toward that end, we propose a genome-wide search to identify a still unknown set of genes that contribute to variation in the behavioral and/or physiologic responses to infection-induced renal disease. These studies will provide critical data necessary to definitively identify the genes that mediate alterations in sleep and to link those genes to other markers of illness. Aim 1 will assess murine strain differences in sleep during toxic nephropathy. Aims 2 and 3 will scan the genome to locate regulatory "hot spots." Aim 4 will capitalize on those findings by assessing the contribution of strong candidate genes. Achieving this ambitious goal is feasible given the experience of my laboratory in surveying sleep phenotypes in other studies involving large numbers of mice.