Bidirectional Relationship Between Growth Hormone and Sleep Following Juvenile TBI

项目摘要/摘要 内分泌疾病(内分泌系统紊乱)越来越被认为是有害的。 创伤性脑损伤的后果。在儿童中，未经治疗的内分泌疾病可能会增加患上 随后的健康问题，包括发育受损、青春期早熟和睡眠-唤醒障碍。《少年派》 最近发表的一项研究表明，患有脑损伤的儿童患后续内分泌疾病的风险更高 与普通儿科人群相比。内分泌疾病患病率最高的是儿童。 7-11岁，是青春期、生长发育的关键时期。本病最常见的诊断是 数据集为青春期改变和生长激素缺乏(GHD)。生长激素(GH)，由 脑下垂体前叶，直接作用于靶组织(如肌肉、器官和骨骼)以刺激生长，并发挥 在睡眠调节中的关键作用。GH的释放在下丘脑多肽的控制下，分泌发生在 全天脉动时尚，最大的生长激素分泌脉冲发生在睡眠中。此外， 患有GHD的人会受到睡眠-唤醒干扰和白天疲劳的困扰。这些睡眠障碍可能 诱发有害的生理效应，进一步抑制生长激素的分泌，并加剧脑损伤的发病率，这 表明生长激素释放和睡眠障碍之间存在双向关系。因此，有一个关键的 需要确定GHD的发生和发展，建立下丘脑的病理时程 并评估其与青少年脑外伤后睡眠障碍的关系。初步结果 来自PI实验室的研究表明，在青春期开始之前，遭受弥漫性脑损伤的大鼠有慢性功能障碍 与未受伤的对照组相比，行为缺陷、下丘脑的病理改变以及较低的生长激素水平。 该研究小组还达成了共识，即实验性脑外伤会导致睡眠障碍。这有 导致了一个中心假设，即青少年实验性脑损伤会导致GHD和睡眠-觉醒障碍 通过对下丘脑神经元的损伤。这一假设将通过以下具体目标进行检验：1) 确定颅脑损伤后GHD的发生和发展，并确定GHD与睡眠的关系。 青少年的觉醒障碍；2)使用刺激性测试来研究生长激素轴的功能以恢复睡眠- 幼年脑外伤后的觉醒活动。这些研究的基本原理是，一旦双向关系 脑外伤后生长激素与睡眠障碍之间的关系、治疗窗口和药理学 靶点可用于限制儿童脑外伤幸存者的发病率。 影响：总而言之，这些研究应该促进对颅脑损伤对生长激素轴和 青少年的睡眠障碍。成功完成拟议的目标将指导精确医学 关于生长激素和睡眠监测在临床决策中的作用的战略，并有可能降低风险 儿童颅脑损伤幸存者中GHD的发生率。

PROJECT SUMMARY/ABSTRACT Endocrinopathies (endocrine system disorders) have increasingly become recognized as deleterious consequences of traumatic brain injury (TBI). In children, untreated endocrinopathies can elevate the risk for subsequent health issues, including impaired growth, precocious puberty, and sleep-wake disturbances. The PI has recently published work that indicated children with a TBI had a higher risk of a subsequent endocrinopathy compared with the general pediatric population. The highest prevalence of endocrinopathies was in children aged 7-11 years, a critical time for puberty, growth, and development. The most common diagnoses in this dataset were altered puberty and growth hormone deficiency (GHD). Growth hormone (GH), released by the anterior pituitary, acts directly on target tissue (e.g., muscle, organ, and bone) to stimulate growth and plays a critical role in sleep regulation. GH release is under the control hypothalamic peptides and secretion occurs in a pulsatile fashion throughout the day, with the largest pulses of GH secretion occurring during sleep. Moreover, individuals with GHD suffer from sleep-wake disturbances and daytime fatigue. These sleep disturbances can elicit detrimental physiological effects, further suppress GH secretion, and exacerbate TBI morbidities, which indicates a bidirectional relationship exists between GH release and sleep disturbances. Thus, there is a critical need to determine the onset and progression of GHD, establish a time course of pathology in hypothalamic neurons, and assess their relationship with sleep disturbances following TBI in juveniles. Preliminary results from the PI’s laboratory demonstrated rats subjected to diffuse TBI, prior to pubertal onset, had chronic functional and behavioral deficits, pathology in the hypothalamus, and lower GH levels compared with uninjured controls. This research team has also established consensus that experimental TBI leads to sleep disturbances. This has led to the central hypothesis that experimental TBI in juveniles results in GHD and sleep-wake disturbances through damage to hypothalamic neurons. This hypothesis will be tested through the following specific aims: 1) Determine the onset and progression of TBI-induced GHD and identify the relationship between GHD and sleep- wake disturbances in juveniles; 2) Investigate the function of the GH-axis using provocative tests to restore sleep- wake activity following juvenile TBI. The rationale for these studies is that once the bidirectional relationship between GH and sleep disturbances after TBI has been identified, therapeutic windows and pharmacological targets could be used to limit the morbidities in pediatric TBI survivors. Impact: Together, these studies should advance the knowledge of TBI-induced damage to the GH-axis and sleep disturbances in juveniles. Successful completion of the proposed aims will guide precision medicine strategies regarding a role for GH and sleep monitoring in clinical decisions, with the potential to reduce the risk of GHD in juvenile TBI survivors.