Bidirectional Relationship Between Growth Hormone and Sleep Following Juvenile TBI

青少年创伤性脑损伤后生长激素与睡眠之间的双向关系

• 批准号: 10358049
• 负责人: RACHEL Kathleen ROWE
• 金额: $ 21.23万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10358049
• 关键词: Bidirectional; Relationship; Between; Growth; Hormone

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.

项目总结/摘要 内分泌疾病（内分泌系统疾病）越来越被认为是有害的 创伤性脑损伤（TBI）。在儿童中，未经治疗的内分泌疾病可增加以下风险： 随后的健康问题，包括发育不良、性早熟和睡眠-觉醒障碍。的PI 最近发表的研究表明，患有TBI的儿童有更高的内分泌疾病风险 与一般儿科人群相比。内分泌疾病的患病率最高的是儿童 7-11岁，青春期、生长发育的关键时期。最常见的诊断是 数据集为青春期改变和生长激素缺乏症（GHD）。生长激素（GH），由 垂体前叶，直接作用于靶组织（例如，肌肉、器官和骨骼）刺激生长， 在睡眠调节中的重要作用。GH的释放受下丘脑肽的控制，分泌发生在下丘脑中。 在一天中，生长激素的分泌呈脉冲状，最大的脉冲发生在睡眠期间。此外，委员会认为， 患有GHD的个体患有睡眠-觉醒障碍和日间疲劳。这些睡眠障碍可以 引起有害的生理效应，进一步抑制GH分泌，并加重TBI发病率， 表明GH释放与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的发病和进展，建立下丘脑病理学的时间过程， 神经元，并评估其与青少年TBI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TBI的大鼠具有慢性功能性 和行为缺陷，下丘脑的病理，和较低的GH水平与未受伤的对照组相比。 该研究小组还建立了共识，即实验性TBI会导致睡眠障碍。这 导致了中心假设，即青少年实验性TBI导致GHD和睡眠-觉醒障碍 通过损害下丘脑神经元。这一假设将通过以下具体目标进行检验：1） 确定TBI诱导的GHD的发作和进展，并确定GHD和睡眠之间的关系- 青少年的觉醒障碍; 2）使用刺激性测试来恢复睡眠， 青少年创伤性脑损伤后的觉醒活动这些研究的基本原理是，一旦双向关系 GH和TBI后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TBI幸存者的发病率。 影响：总之，这些研究应该推进TBI引起的GH轴损伤的知识， 青少年睡眠障碍成功完成拟议目标将指导精准医学 关于GH和睡眠监测在临床决策中的作用的策略，具有降低风险的潜力 青少年创伤性脑损伤幸存者的生长激素缺乏症