Bruce G. Lyeth - US grants

neurotransmitter receptor; receptor coupling; head /neck injury; brain injury; trauma; long term potentiation; inositol phosphates; psychomotor function; phospholipase C; calcium flux; brain metabolism; neuropharmacology; diacylglycerols; receptor binding; glutamate receptor; muscarinic receptor; behavior test; hippocampus; laboratory rat; disease /disorder model;

DESCRIPTION (Adapted from Applicant's Abstract): Glutamate toxicity, mediated via ion channel-linked receptor plays a well established, key role in traumatic brain injury (TBI) pathology and behavioral morbidity. In addition to activation of ionotropic receptors, excessive glutamate released by injury also activates G-protein-linked, metabotropic glutamate receptors (mGluRs). However, the contribution of mGLuR activation on TBI- induced glutamate excitotoxicity has not been systematically examined and remains unclear. TBI-induced activation of mGluR cm theoretically increase excitotoxicity or decrease excitotoxicity depending upon the subtype of mGluR activated. The long term objectives of this research are to investigate the extent of, and the mechanisms by which mGluRs influence TB pathophysiological processes. Behavioral, neurochemical, histological, and electrophysiological studies will examine the functional role of mGluRs in TBI pathophysiology using a well characterized, fluid percussion model of brain injury in the rat. By selectively stimulating or blocking selected subtypes of receptors during the injury process, mechanisms of mGluR pathology and pharmacological neuroprotection will be examined using in vivo microdialysis, receptor binding, western blot and immunohistochemistry, and functional measures of receptor-second messenger coupling. This research will provide new and important insights into glutamate excitotoxicity and receptor mediated pathophysiology in brain injury processes. This research will also provide clinically relevant information about potential pharmacological agents for the treatment of human head injury.

DESCRIPTION (provided by applicant): The long-term objective of this research is to examine mechanisms of acute astrocyte damage and death following traumatic brain injury and to develop treatment strategies for attenuating these injury mechanisms. We address anatomical and functional consequences of traumatic brain injury using neuroanatomical, neuroimaging, and behavioral techniques with the goal of understanding the pathological mechanism and developing therapeutic strategies. Traumatic brain injury is a significant health problem that results in more than 230,000 hospitalizations and 50,000 deaths per year in the USA. Survivors of TBI are often left with long-term disability. Astrocytes are the most numerous type of gila cells and provide many important functions to support neurons including exchange of metabolic and nutritional material, clearance of neurotransmitters, and maintenance of ion concentrations in the vicinity of neurons. Astrocyte function is likely to have great importance after traumatic brain injury when extracellular glutamate and potassium concentrations are elevated. Severe damage to astrocytes occurs within hours after traumatic brain injury in brain regions that later exhibit significant neuronal cell degeneration and loss. We hypothesize that the early damage to astrocytes is due, in part, to large increases in intracellular sodium that enter astrocytes through sodium-dependent glutamate transporters and by activation of the type 1 sodium proton exchanger. The resulting increased intracellular sodium promotes reversal of the astrocyte sodium-calcium exchanger creating an excess of intracellular calcium that ultimately leads to astrocyte death. We will test and refine these hypotheses using established cell culture injury models. We will subject cells to traumatic injury and manipulate various sodium and calcium transporters while measuring intracellular ion concentrations and cell viability. This information will be used to explore novel pharmacological manipulations targeted at these sodium and calcium injury mechanisms. In these in vivo therapeutic studies we will measure astrocyte and neuronal viability using anatomical markers, measure brain edema using magnetic resonance imaging, and measure functional outcome using behavioral measures of sensorimotor function and learning and memory following traumatic brain injury in the rat.

[unreadable] DESCRIPTION (provided by applicant): We are requesting support for basic science graduate students, medical students, residents and postdoctoral fellows to participate in the 25th annual National Neurotrauma Symposium. The National Neurotrauma Symposium is the primary forum for the presentation of the most current research on the pathophysiology and treatment of central nervous system injury. The Specific Aims of the 25th annual National Neurotrauma Symposium (2007) are: 1. To provide a forum for the presentation, discussion and feedback regarding the most recent findings in Neurotrauma research and to encourage interaction between those new to the field and those with extensive experience. 2. To have relevant and thought-provoking presentations by researchers not directly involved in Neurotrauma research. The goal is to foster new ideas and ways of thinking into mainstream Neurotrauma as well as to encourage scientist from other disciplines to engage in Neurotrauma research. 3. To encourage the participation and education of students studying in the field of Neurotrauma. The Symposium fosters student participation through large poster sessions, student oral open-communication sessions, student poster competition, social mixers, student travel awards, and subsidized student registration fees. 4. To continue to encourage the involvement of researchers from women and minority groups in Neurotrauma research. The Symposium is the forum for scientific and social activities hosted by Women in Neurotrauma Research, the professional society for women in clinical and laboratory Neurotrauma research The program for the 2007 Symposium will feature 21 invited lectures, 12 oral presentations of selected student/postdoctoral abstracts, 4 poster sessions with a total of approximately 300 posters, and a student poster competition. The presentation of these exciting new areas will foster Neurotrauma research that will lead to new techniques for the treatment and rehabilitation of patients afflicted with head and spinal cord injury. The direct relevance of this project to public health rests in the exchange of new ideas and the debate generated regarding advancing laboratory findings into clinical practice. Students, basic scientists, clinician-scientists, and practicing clinicians come together to present and discuss their latest discoveries and advancements in the field of Neurotrauma. Particular efforts are made to actively engage students to participate and interact with leading basic scientists and clinicians. [unreadable] [unreadable] [unreadable]