This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The science of this proposal addresses the overarching hypothesis that energy-substrate metabolism within select populations of hypothalamic cells is an important component of nutrient-sensing in the central nervous system. Further, it is proposed that hypothalamid nutrient sensing determines an organism's capacity to maintain appropriate energy homeostasis. This broad hypothesis envelops a range of human health issues from chronic determinants of obesity to acute factors of glucose-counter-regulation in diabetes mellitus. More narrowly defined hypotheses to be addressed include the idea that cellular glycolytic flux along with intracellular ratios of adenosine-phosphate nucleotides contributes to hypothalamic neuronal signaling, either in terms of the strength of outgoing signals from neurons, or sensitivity to incoming signals. Along with this idea is the hypothesis that antecedent environmental factors, such as prolonged cellular exposure to high levels of glucose can alter the gain of nutrient sensing hypothalamic systems by altering the levels of gene expression, or by altering the activity of previously described cellular proteins. Findings from our studies could have a significant impact on understanding disorders such as failed hypoglycemic counter-regulation. The specific hypotheses of this proposal contend that a portion of neurotransmitter release from hypothalamic glucose-sensing neurons is modulated by the coordinated actions of a set of proteins that include glucokinase (GK) (hexosekinase IV), ATP-sensitive K+channels, adenylate kinase and AMPK. These proteins can regulate the rate of glycolysis and control adenosine phosphate (AMP/ATP) ratios. The scientific specific aims of this proposal are as follows:
Specific Aim 1 : To extend our previous ex-vivo hypothalamic neurotransmitter release studies by providing additional evidence on the identities and mechanisms of neurotransmitters affected by K+ATP channel activity.
Specific Aim 2 : To develop a CNS cell culture model as a means of rapidly testing multiple facets of the hypothesis that alterations in putative glucose sensing molecules occur in response to alterations in ambient nutrient conditions.
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