Project Summary: Growth hormone deficiency (GHD) due to chronic traumatic brain injury (TBI) is common among the veterans from the wars in Iraq and Afghanistan. Such condition develops as a result of hypothalamic-pituitary axis (HPA) dysfunction leading to reduced growth hormone (GH) levels, which pose a significant impact on their quality of life due to medical, psychological, and psychiatric consequences. The GH replacement therapy in post-traumatic GHD, in most cases, do not produce the desired clinical outcome. Analysis of the signs and symptoms of HPA dysfunction suggests that compromise in GH secretion may be as a result of defective upstream hypothalamic signaling. Thus, we propose to restore the hypothalamic- neurotropic stimulation by endogenous GH secretion from the surviving (post-TBI) anterior pituitary cells (somatotrophs), leading to axonal regeneration of TBI-damaged neurons. Although intracellular calcium ion (Ca2+) concentration ([Ca2+]i) can regulate hormone release, the ion channel responsible for increasing [Ca2+]i the GH release in pituitary somatotrophs is unknown. Our ongoing studies have identified that activation of Transient Receptor Potential Canonical 3 (TRPC3), a Ca2+ influx channel, facilitates vesicle-associated soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein complex interactions, which is necessary for hormonal release. Moreover, disruption of TRPC3 markedly attenuated [Ca2+]i entry, which is essential for GH secretion and axonal regeneration. Thus, our central hypothesis is that the agonist activation of TRPC3 in pituitary cells triggers Ca2+ entry, resulting in enhanced GH secretion, which will help to regenerate those damaged axons in the adjacent HPA region. We propose to study the following two Aims using an established controlled cortical impact (CCI)-induced injury mouse model of TBI: (1) Characterization of the role of TRPC3 in regulating GH secretion by examining the functional restoration of hypothalamic neurotropic connections in TBI; and (2) Determine that TRPC3 activation stimulates axonal regeneration in TBI-damaged neurons and examine a “proof of concept” that augmenting TRPC3 expression/activation ameliorates chronic neurobehavioral abnormalities. We will perform a series of behavioral tests such as Morris water maze for memory and beam walk test to assess sensorimotor coordination and motor learning for correlating the behavior with brain neurochemistry. The results of the present study will: i) find the novel mechanism of TRPC3-induced GH secretion essential for axonal growth and regeneration that can be used as a tool to identify potential new therapeutic options; ii) elucidate the molecular pathogenesis of GH secretion following chronic TBI; and iii) help to plan and execute future investigations to improve and manage TBI- induced GHD and neurobehavioral abnormalities in both veterans and civilians.