This is a rerevised, competitive renewal application (HL66023) that continues our examination of the physiologic relevance of recently described neuropeptides which we have demonstrated to act at least pharmacologically to stimulate stress hormone secretion (prolactin, PRL, and adrenocorticotropin, ACTH) by a brain site of action. Additionally, these peptides stimulate stress-related behavioral responses (activity) and at least one acts in brain to stimulate sympathetic activity resulting in increased blood pressure. These peptides (prolactin releasing peptide, PrRP;neuropeptide W, NPW;and neuropeptide B, NPB) are produced in separate populations of neurons in brain, many of which innervate the hypothalamic paraventricular nucleus (PVN), arcuate nucleus (ARC) and ventromedial and dorsomedial hypothalamic nuclei (VMH/DMH). All three peptides are contained in neurons that innervate autonomic centers in hypothalamus and brain stem. It is our goal to understand the roles these peptides play in the hypothalamic and extrahypothalamic responses to stress. We address multiple specific aims all related to the founding hypothesis that one or more of these peptides is essential for the endocrine and/or cardiovascular response to stress, under certain paradigms of stress. Our approach will be to demonstrate direct effects of these peptides on identified fore- and hindbrain neurons [e.g. in PVN, ARC, VMH/DMH, nucleus tractus solitarius (NTS), rostral lateral medulla (RVLM), and dorsal motor nucleus of the Vagus] using electrophysiologic, pharmacologic and single cell RT- PCR approaches. We will then attempt compromise of peptide production and examine hormone secretion in response to physical stress and the cardiovascular response to hypertensive and hypotensive challenge (i.e. baroreflex sensitivity). Understanding the normal mechanisms controlling the response to stress will reveal potential strategies for the management of stress in the human population and the cardiovascular and metabolic consequences of that stress. These studies may also provide insight into the central mechanisms contributing to development of the metabolic syndrome (Syndrome X), which is characterized by obesity, poor glycemic control, altered metabolic and autonomic function and a propensity for adverse cardiovascular outcomes. Additionally, these studies will provide further insight into the coordinated hormonal and autonomic responses to stress.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066023-07
Application #
7789408
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Mcdonald, Cheryl
Project Start
2001-06-01
Project End
2013-03-31
Budget Start
2010-04-01
Budget End
2013-03-31
Support Year
7
Fiscal Year
2010
Total Cost
$305,969
Indirect Cost
Name
Saint Louis University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Yosten, Gina L C; Liu, Jun; Ji, Hong et al. (2016) A 5'-upstream short open reading frame encoded peptide regulates angiotensin type 1a receptor production and signalling via the ?-arrestin pathway. J Physiol 594:1601-5
Samson, Willis K; Stein, Lauren M; Elrick, Mollisa et al. (2016) Hypoglycemia unawareness prevention: Targeting glucagon production. Physiol Behav 162:147-50
Yosten, Gina L C; Elrick, Mollisa M; Salvatori, Alison et al. (2015) Understanding peptide biology: The discovery and characterization of the novel hormone, neuronostatin. Peptides 72:192-5
Yosten, Gina L C; Samson, Willis K (2014) Neural circuitry underlying the central hypertensive action of nesfatin-1: melanocortins, corticotropin-releasing hormone, and oxytocin. Am J Physiol Regul Integr Comp Physiol 306:R722-7
Liu, Jun; Yosten, Gina L C; Ji, Hong et al. (2014) Selective inhibition of angiotensin receptor signaling through Erk1/2 pathway by a novel peptide. Am J Physiol Regul Integr Comp Physiol 306:R619-26
Yosten, Gina L C; Kolar, Grant R; Redlinger, Lauren J et al. (2013) Evidence for an interaction between proinsulin C-peptide and GPR146. J Endocrinol 218:B1-8
Yosten, G L C; Lyu, R-M; Hsueh, A J W et al. (2013) A novel reproductive peptide, phoenixin. J Neuroendocrinol 25:206-15
Pate, A T; Yosten, G L C; Samson, W K (2013) Compromise of endogenous neuropeptide W production abrogates the dipsogenic and pressor effects of angiotensin II in adult male rats. J Neuroendocrinol 25:1290-7
Yosten, Gina L C; Kolar, Grant R; Redlinger, Lauren J et al. (2013) Evidence for an interaction between proinsulin C-peptide and GPR146. J Endocrinol 218:B1-8
Pate, Alicia T; Yosten, Gina L C; Samson, Willis K (2013) Neuropeptide W increases mean arterial pressure as a result of behavioral arousal. Am J Physiol Regul Integr Comp Physiol 305:R804-10

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