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

摘要 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，导致 死亡或严重残疾的一生。早期肌肉萎缩是脊髓损伤的地方性后果， 导致死亡、功能恢复受损和继发性并发症的发生。当前干预措施 直到在急性护理期间已经发生了相当大的肌肉萎缩之后才开始，并且是最低限度的 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来保护 在脊髓损伤和康复之间的关键急性期，肌肉和防止消瘦。尽管 失神经和瘫痪肌肉的不活动是肌肉萎缩的常见解释，但它们不能 解释脊髓损伤后早期出现的非瘫痪肌肉萎缩的原因。有趣的是，高胸段脊髓损伤 与下胸水平相比，同时加剧急性皮质醇增多和全身肌肉萎缩 急性下胸段脊髓损伤时一过性皮质醇增多与一过性非瘫痪肌肉相对应 消瘦，而进行性皮质醇亢进对应于持续的非瘫痪肌肉消瘦 急性上胸段脊髓损伤。脊髓损伤水平依赖的皮质醇增多症代表一种全身性候选信号 加剧全身肌肉萎缩，因为糖皮质激素会导致肌肉萎缩。这项研究将 探讨急性脊髓损伤水平依赖的皮质醇增多症的原因，并确定是否保护肌肉 糖皮质激素可减轻急性高位胸段脊髓损伤时全身肌肉的损耗。基于飞行员 数据，研究人员的目标是确定脊髓损伤水平依赖的急性皮质醇增多症是否由 对肾上腺功能的交感神经控制有偏差。下丘脑-垂体-肾上腺(HPA)轴激素 上、下胸段脊髓损伤急性期轴心功能和肾上腺糖皮质激素合成 有侧写。然后，将研究是否保护肾上腺不受脊髓交感神经反射活动的影响。 交感神经切断可减轻脊髓损伤水平依赖性的皮质醇增多症。随后，调查人员 将决定是否通过药理糖皮质激素预防肌肉接触糖皮质激素 受体(GR)拮抗或敲除肌肉GR可减轻脊髓损伤水平依赖的肌肉萎缩严重程度， 由肌肉质量、肌肉功能、肌肉成分和基因/蛋白质表达决定 肌肉消耗调节剂的量化。这项研究将由一名医学博士/博士研究生在 监督脊髓损伤研究领域的2名领导者，并与3名神经肌肉专家合作。这个 MD/PHD课程已经很好地建立起来了，并且在SCI、Myology方面的制度环境非常强大 以及内分泌研究。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，以及创造性和严谨的实验 在SCI领域追求独立研究事业所必需的设计。

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.