Interrogating adrenal dysfunction to prevent muscle wasting after acute spinal cord injury

总结 创伤性脊髓损伤（SCI）是一种毁灭性的疾病，每年影响约18，000名美国人， 死亡或终身严重残疾。早期肌肉萎缩是脊髓损伤的一种地方性后果， 死亡率、功能恢复受损和继发性并发症的发生。目前的干预措施 直到在急性护理期间已经发生相当大的肌肉萎缩之后才开始， 有效为了降低死亡率和最大限度地提高生活质量，需要基于机制的干预措施， 在SCI和康复之间的关键急性期“桥接”期间，虽然 麻痹肌肉的去神经支配和不活动是肌肉萎缩的常见解释，它们不能 解释了SCI后早期发生的非瘫痪肌肉的萎缩。有趣的是，高胸段脊髓损伤 与低胸水平相比，同时加重急性皮质醇增多症和全身肌肉萎缩 SCI;急性下胸部SCI期间一过性皮质醇增多症与一过性非麻痹肌肉相对应 消耗，而进行性皮质醇增多症对应于持续的非麻痹性肌肉消耗， 急性高位胸椎脊髓损伤SCI水平依赖性皮质醇增多症是一个系统性候选信号 由于糖皮质激素有效地诱导肌肉萎缩，从而加剧全身肌肉萎缩。这项研究将 研究急性SCI水平依赖性皮质醇增多症的原因，并确定是否保护肌肉 减少急性高位胸段脊髓损伤时全身肌肉的消耗。基于导频 数据，研究人员的目的是确定是否SCI水平依赖性急性皮质醇增多症的结果， 交感神经对肾上腺功能的扭曲控制下丘脑-垂体-肾上腺轴激素 轴功能和肾上腺糖皮质激素的合成在急性期的高，低胸部SCI将是 侧写然后，将研究是否屏蔽肾上腺脊髓交感神经反射活动 通过交感神经去支配减弱SCI水平依赖性皮质醇增多症。随后，调查人员 将确定是否通过药理学糖皮质激素来防止肌肉暴露于糖皮质激素， 受体（GR）拮抗或肌肉GR的敲除减弱了SCI水平依赖性肌肉萎缩的严重程度， 通过测量肌肉质量、肌肉功能、肌肉组成和基因/蛋白质表达来确定 肌肉消耗介质的定量。这项研究将由一名MD/PhD候选人根据 2名SCI研究领域的领导者的指导，并与3名神经肌肉专家合作。的 MD/PhD课程已经建立，并且机构环境在SCI，肌肉学 内分泌研究。培训计划包括发展基础科学知识的机会， 知识、独立性、技术专长、沟通能力、创造性和严谨的实验 在SCI领域从事独立研究所必需的设计。

SUMMARY Traumatic spinal cord injury (SCI) is a devastating condition that affects ~18,000 Americans annually, resulting in death or a lifetime of severe disability. Early muscle wasting is an endemic consequence of SCI that contributes to mortality, impaired functional recovery and the development of secondary complications. Current interventions are not started until after considerable muscle wasting has already occurred during acute care and are minimally effective. To reduce mortality and maximize quality of life, mechanism-based interventions are needed to protect muscle and prevent wasting during the critical acute period ‘bridging’ between SCI and rehabilitation. Though denervation and inactivity of paralyzed muscles are common explanations for muscle wasting, they cannot explain the wasting of non-paralyzed muscles that occurs early after SCI. Interestingly, high thoracic level SCI concurrently exacerbates acute hypercortisolism and systemic muscle wasting, compared to low thoracic level SCI; Transient hypercortisolism during acute low thoracic SCI corresponds with transient non-paralyzed muscle wasting, whereas progressive hypercortisolism corresponds with enduring non-paralyzed muscle wasting during acute high thoracic SCI. SCI level-dependent hypercortisolism represents a systemic candidate signal exacerbating systemic muscle wasting since glucocorticoids potently induce muscle wasting. This research will investigate the cause of acute SCI level-dependent hypercortisolism and determine whether protecting muscle from glucocorticoids attenuates systemic muscle wasting during acute high thoracic level SCI. Based on pilot data, the investigators aim to determine whether SCI level-dependent acute hypercortisolism results from skewed sympathetic control over adrenal function. Hypothalamic-pituitary-adrenal (HPA)-axis hormones, HPA- axis function, and adrenal glucocorticoid synthesis during the acute phase of high and low thoracic SCI will be profiled. Then, it will be investigated whether shielding the adrenal glands from spinal sympathetic reflex activity by sympathetic denervation attenuates SCI level-dependent hypercortisolism. Subsequently, the investigators will determine whether preventing muscle exposure to glucocorticoids through pharmacological glucocorticoid receptor (GR) antagonism or knockout of muscle GR attenuates SCI level-dependent muscle wasting severity, as determined by measures of muscle mass, muscle function, muscle composition and gene/protein expression quantification of muscle wasting mediators. This research will be conducted by an MD/PhD candidate under the supervision of 2 leaders in the field of SCI research and in collaboration with 3 neuromuscular experts. The MD/PhD program is well established, and the institutional environment is exceptionally strong in SCI, myology and endocrine research. The training plan consists of opportunities to develop the foundational scientific knowledge, independence, technical expertise, communication skills, and creative and rigorous experimental design necessary to pursue an independent research career in the field of SCI.