We recently showed that stress increases the levels of diacylglycerol (DAG) and Protein Kinase C (PKC) in synaptosomes from the brain of animals stressed by sleep deprivation. The centerpiece of our study is that REM sleep deprivation elicits a generalized systemic stress response involving the HPA axis and the activation of POMC-derived peptides, biogenic amines, their receptors, specific kinases, stress proteins and specific genes within the cardiovascular system as well as selected regions of the central nervous system (CNS) and the autonomic nervous system (ANS) that are responsible for regulating cardiovascular function. Therefore, our working hypotheses in this project are: (1) stress increases the levels of proopiomelanocortin (POMC)-derived peptides, in particular, gamma-2-MSH and ACTH[1-39]; (2) that these increases can be correlated with increases in blood pressure and heart rate; (3) that there are specific proteins kinases that are activated during stress and the activation of these protein kinases are further enhanced following stimulation with POMP- derived peptides; (4) there are specific stress proteins that are induced in response to stress; and (5) there are specific POMC genes that are activated in response to stress and these POMC genes are colocalized within the same cells. Since this is a multi-investigator, interdisciplinary approach, the goal of this project is to assemble a critical mass of faculty with research interest in Stress and Cardiovascular Diseases to conduct investigations into the cellular, molecular, chemical, physiological and behavioral mechanisms underlying Stress and Cardiovascular Diseases. The involvement of the faculty members will be as follows: (1) Dr. Robinson, as activity leader and Program Director will be responsible for the overall research program. (2) Dr. Robinson and Dr. Koban will focus on determining the levels of POMC- derived peptides, in particular gamma-2-MSH and ACTH[1-39] and catecholamines in the plasma of animals stressed by sleep deprivation and examine whether these changes are correlated with changes in cardiovascular parameters. Dr. Hughes will focus on identifying whether specific protein kinases (aim 2) and specific genes (aim 3) are induced following sleep deprivation and whether POMC-derived peptides increases the induction of these enzymes. Dr. Robinson will assist Dr. Hughes in the immunocytochemical and in situ hybridization studies involved in these aims. Dr. Koban will focus on identifying the specific stress proteins that are induced during stress by sleep deprivation (aim 2b-i) and Dr. Delauder will focus on the physical properties of stress proteins and their interactions with dopamine-beta-hydroxylase in A #2b-ii.
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