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.

R21NS120022

2020-09-30

2022-08-31