Baroreceptor and chemoreceptor reflexes are actively involved in the control of fetal blood pressure and in the maintenance of blood flow to the placenta and to the metabolizing tissues. The present project is an investigation into the mechanism of the baro-and chemoreflexes. In previous funding periods of this project, we discovered and explored the interaction between changes in fetal blood pressure and prostaglandin generation in the fetal brain. We have discovered that COX-2 expression in the brain is controlled in both site- and development- specific patterns, and that blockade of COX-2 decreases the neuroendocrine responsiveness to cerebral hypoperfusion. The expression of COX-2 is not dependent upon cellular hypoxia, but is dependent upon NMDA-glutamatergic neurotransmission. Our most recent data indicate that COX-2 is one component of an inflammatory cascade that is activated by hypoxia and cerebral hypoperfusion, and that the activation of this cascade is associated with upregulation of the apoptosis pathways. Based on these results, we have proposed three specific aims in the renewal of this project: 1) to test the hypothesis that ACTH and Arginine Vasopressin (AVP), but not autonomic nervous system responses to BCO, isocapnic hypoxic hypoxia (HH), and partial umbilical cord occlusion (UCC) are inhibited by NMDA receptor blockade and that the degree of inhibition correlates to cellular activity in brain regions and nuclei subserving sensation and integration of the reflex responses;2) to test the hypothesis that BCO, HH, and UCC all increase inflammatory pathways in the fetal PVN, midbrain nuclei, medullary nuclei, and IML, and that the increase in inflammatory marker expression is in part dependent upon NMDA signaling;and 3) to test the hypothesis that BCO, HH, and UCC all increase apoptosis in various brain regions, and that blockade of NMDA receptors will ameliorate this outcome. In the proposed 5-year continuation of this project, we will use and innovative combination of whole animal, molecular, genomics, and informatics techniques to identify the heretofore unappreciated link between alterations in O2 and CO2, activation of NMDA-glutamatergic neurotransmission, stimulation of brain inflammation, and stimulation of cellular apoptosis and long-term impairment of brain function. The results are likely to demonstrate the importance of NMDA receptor blockade as a neuroprotective strategy in late gestation fetuses and for premature infants in the NICU.

Public Health Relevance

This project examines the possibility that fetal hypoxia, asphyxia, and ischemia all stimulate brain inflammation, apoptosis, and cell death that is dependent on an increase in NMDA- glutamatergic neurotransmission that mediates the physiologic and endocrine reflex responses to the stressors.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD033053-17
Application #
8606478
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Ilekis, John V
Project Start
1996-05-03
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
17
Fiscal Year
2014
Total Cost
$295,476
Indirect Cost
$93,786
Name
University of Florida
Department
Physiology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Wood, Charles E; Rabaglino, Maria Belen; Richards, Elaine et al. (2014) Transcriptomics of the fetal hypothalamic response to brachiocephalic occlusion and estradiol treatment. Physiol Genomics 46:523-32
Rabaglino, Maria B; Keller-Wood, Maureen; Wood, Charles E (2014) Transcriptomics of the late gestation ovine fetal brain: modeling the co-expression of immune marker genes. BMC Genomics 15:1001
Wood, Charles E; Rabaglino, Maria Belen; Chang, Eileen I et al. (2013) Genomics of the fetal hypothalamic cellular response to transient hypoxia: endocrine, immune, and metabolic responses. Physiol Genomics 45:521-7
Wood, Charles E; Keller-Wood, Maureen (2011) Influence of estradiol and fetal stress on luteinizing hormone, follicle-stimulating hormone, and prolactin in late-gestation fetal sheep. Neonatology 100:155-61
Fraites, Melanie J P; Wood, Charles E (2011) Chemoreflex activity increases prostaglandin endoperoxide synthase mRNA expression in the late-gestation fetal sheep brain. Reprod Sci 18:824-31
Knutson, Nathan; Wood, Charles E (2010) Interaction of PGHS-2 and glutamatergic mechanisms controlling the ovine fetal hypothalamus-pituitary-adrenal axis. Am J Physiol Regul Integr Comp Physiol 299:R365-70
Gersting, Jason A; Schaub, Christine E; Wood, Charles E (2009) Development of prostaglandin endoperoxide synthase expression in the ovine fetal central nervous system and pituitary. Gene Expr Patterns 9:603-11
Wood, Charles E; Powers Fraites, Melanie; Keller-Wood, Maureen (2009) Blockade of PGHS-2 inhibits the hypothalamus-pituitary-adrenal axis response to cerebral hypoperfusion in the sheep fetus. Am J Physiol Regul Integr Comp Physiol 296:R1813-9
Wood, Charles E (2008) Cerebral hypoperfusion increases estrogen receptor abundance in the ovine fetal brain and pituitary. Neuroendocrinology 87:216-22
Schaub, Christine E; Gersting, Jason A; Keller-Wood, Maureen et al. (2008) Development of ER-alpha and ER-beta expression in the developing ovine brain and pituitary. Gene Expr Patterns 8:457-63

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