Traumatic brain injury (TBI) is characterized by a sudden concussive (direct force or shock wave) blow to the head, in which traumatic biomechanical forces are transferred throughout the head and neck. Damage to neural tissue occurs due to rapid acceleration and deceleration forces of the brain, culminating upon impact of the brain with the interior of the skull. At the molecular level, TBI generates a host of physiological responses, which manifest in many different ways. The focus of this thesis will be on the trajectory that progresses through 1) brain acceleration forces, 2) force-induced DNA damage in neurons and glia, 3) activation of DNA repair mechanisms (specifically, poly ADP-ribose polymerase (PARP)), 4) nicotinamide adenine dinucleotide (NAD +) depletion via PARP assembly, 5) the effect of NAD + depletion on energy metabolism, and 6) the potential value of an NAD+ modulator (nicotinamide riboside chloride, NR-Cl) in modulating this effect. Pathologically, reactive oxygen species (ROS) and other free radicals are generated following TBI. The generation of these radicals leads to DNA damage in affected regions of the brain. In response to DNA damage, PARP, a molecule responsible for initiating DNA repair, is activated and begins to polymerize. The assembly of PARP is directly dependent upon nicotinamide adenine dinucleotide (NAD+) cannibalization, in which the ADP-ribosyl subunit of NAD+ is used to build the large poly ADP-ribose (PAR) polymer. One PAR assembly can consume up to 200 ADP-ribose subunits derived from NAD+. This leads to depleted cellular NAD + and diminished energy metabolism, the severity of which is dependent upon the extent of injury and degree of PARP activation. In this thesis, I will summarize the molecular mechanisms associated with PARP activation, NAD + depletion, energy dysregulation, and the potential value of NR-Cl as a potential therapeutic agent in mild and moderate TBI.
|Advisor:||Briehl, Margaret M.|
|Commitee:||Darnell, Diana K., Gordon, Herman|
|School:||The University of Arizona|
|Department:||Cellular and Molecular Medicine|
|School Location:||United States -- Arizona|
|Source:||MAI 58/04M(E), Masters Abstracts International|
|Subjects:||Neurosciences, Biochemistry, Medicine|
|Keywords:||Concussion, NAD+ depletion, Neuronal energy dysregulation, Nicotinamide riboside, PARP, Traumatic brain injury|
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