Project Summary/AbstractEndocrinopathies (endocrine system disorders) have increasingly become recognized as deleteriousconsequences of traumatic brain injury (TBI). In children untreated endocrinopathies can elevate the risk forsubsequent health issues including impaired growth precocious puberty and sleep-wake disturbances. The PIhas recently published work that indicated children with a TBI had a higher risk of a subsequent endocrinopathycompared with the general pediatric population. The highest prevalence of endocrinopathies was in childrenaged 7-11 years a critical time for puberty growth and development. The most common diagnoses in thisdataset were altered puberty and growth hormone deficiency (GHD). Growth hormone (GH) released by theanterior pituitary acts directly on target tissue (e.g. muscle organ and bone) to stimulate growth and plays acritical role in sleep regulation. GH release is under the control hypothalamic peptides and secretion occurs in apulsatile fashion throughout the day with the largest pulses of GH secretion occurring during sleep. Moreoverindividuals with GHD suffer from sleep-wake disturbances and daytime fatigue. These sleep disturbances canelicit detrimental physiological effects further suppress GH secretion and exacerbate TBI morbidities whichindicates a bidirectional relationship exists between GH release and sleep disturbances. Thus there is a criticalneed to determine the onset and progression of GHD establish a time course of pathology in hypothalamicneurons and assess their relationship with sleep disturbances following TBI in juveniles. Preliminary resultsfrom the PIs laboratory demonstrated rats subjected to diffuse TBI prior to pubertal onset had chronic functionaland 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 hasled to the central hypothesis that experimental TBI in juveniles results in GHD and sleep-wake disturbancesthrough 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 relationshipbetween GH and sleep disturbances after TBI has been identified therapeutic windows and pharmacologicaltargets 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 andsleep disturbances in juveniles. Successful completion of the proposed aims will guide precision medicinestrategies regarding a role for GH and sleep monitoring in clinical decisions with the potential to reduce the riskof GHD in juvenile TBI survivors.