Top
|
 |
Flouret, George | Levine, Jon | McDade, Thomas | Redei, Eva | Woolley, Catherine
My
research is in the area of peptide hormone synthesis, breakdown and mode of action. We
have synthesized many agonists and antagonists of LHRH, which is a peptide messenger
secreted by the brain, and which controls the secretion of LH and FSH by the anterior
pituitary. Several of the LHRH antagonists we have designed have strong antiovulatory
activity, and we are studying their susceptibility to enzymatic breakdown in various
tissues, in vivo or in vitro. We have also designed highly potent oxytocin antagonists
(OTAs), with the aim of inhibiting preterm labor. OT is one of the hormones that promote
the contractions of labor. Some of our antagonists may be the most potent OTAs yet
designed and successfully inhibit labor in the rat and the baboon. We are also
investigating the binding of OT and OTAs by uterine receptors. An understanding of the
characteristics of peptide hormone binding to receptors in target tissues as well as the
mechanisms of enzymatic degradation of these substances enhances the likelihood that
antagonists which have clinical significance may be developed both for LHRH and OT.
Recent Publications:
Flouret G, Brieher W, Majewski T, Wilson Jr 1991 Some pharmacological properties of cyclic and linear analogs obtained by substituting each residue of an oxytocin antagonist with D-tryptophan. Int J Peptide and Protein Res 38:169-175.
Flouret G, Mahan K, Majewski T 1992 Decreased Histamine release by LHRH antagonists obtained upon translocation of the cationic amino acid from position 8 to position 7. J Med Chem 35:636-640.
Fejgin MD, Pak SC, Flouret G, Wilson Jr L 1994 Oxytocin antagonist inhibitory effect in the baboon and rat uterus may be overcome by the use of prostaglandins. Am J Obstet Gynecol 171:1076-1080.
Fak SC, Bertoncini D, Meyer W, Scaunas D, Flouret G, Wilson Jr L 1994 Comparison of binding affinity of oxytocin antagonists to human and rat uterine oxytocin receptors and their correlation to the rat uterine oxytocic bioassay. Biol Reprod 51:1140-1144.
Flouret G, Arnold ZS,
Majewski T, Petousis NH, Mahan K, Farooqui F, Blum KA, Konopinska D, Natarajan S, Crich D
1995 Antiovulatory Antagonists of LHRH related to Antide. J Peptide Sci
1:89-105.
Top | Email Me | Dept. Home Page
Top
|
|
We are
particularly interested in the activity of neurons that synthesize and release
luteinizing hormone-releasing hormone (LHRH), a decapeptide that mediates hypothalamic
regulation of pituitary gonadotropes, thereby controlling ovulatory cycles and other
critical reproductive functions. Our studies also focus on other important neuromodulators
of reproductive function, such as neuropeptideY (NPY). To study the activity of these and
other peptidergic cell groups, we use in vivo microdialysisas well as in vitro superfusion
of tissue and cell cultures to measure the ongoing release of peptideregulators under
various physiological and pharmacological conditions. In situ hybridization andrelated
molecular technologies are also used to analyze the physiological regulation of gene
expression in these neurons. Three basic aspects of hypothalamic neuropeptide function are
examined: the intrinsic cellular activities of these systems (e.g., mechanisms regulating
pulsatile release patterns), the regulation of pituitary hormone secretion by hypothalamic
peptidergic neurons, and the regulation of peptide neurosecretion and gene expression by
hypothalamic neurotransmitters and gonadal steroid feedback mechanisms. Integrated studies
at these three levels are directed at understanding basic reproductive processes, such as
the generation of preovulatory gonadotropin surges. A midcycle surge of gonadotropins
provides the endocrine trigger for ovulation in virtually all mammals and is dependent
upon the sufficient and appropriate release of LHRH and other hypothalamic regulators,
such as NPY. We are therefore attempting to gain a detailed understanding of the cellular
mechanisms governing thesynthesis, release, and actions of these peptides throughout this
critical periovulatory period. In other related studies, the participation of LHRH, NPY,
and other peptidergic cell groups in homeostaticgonadal feedback mechanisms and
photoperiodic regulation of the reproductive axis are also being examined. A long-term
goal of this laboratory is to understand how these neuropeptidergic systems can coordinate
several neural and endocrine activities to produce an appropriate homeostatic state, such
as reproductive competency. It is also hoped that our studies may ultimately provide
useful information in the treatment of some forms of infertility and in the development of
new contraceptive strategies.
Recent Publications:
Besecke LM, Wolfe AM, Pierce M, Takahashi T, Levine JE 1994 Neuropeptide Y (NPY) stimulates luteinizing hormone-releasing hormone (LHRH) release from superfused, hypothalmic GT1-7 cells. Endocrinology 135:1621-1627.
Urban JH, Das I, Levine JE 1996 Steroid modulation of neuropeptide Y-induced luteinizing hormone-releasing hormone release from median eminence fragments from male rats. Neuroendocrinology 63:112-119.
Levine JE 1997 New concepts of the neuroendocrine regulation of gonadotropin surges in rats. Invited review and commentary (Summary of President’s symposium presentation, 29th Annual Meeting of the Society for the Study of Reproduction). Biology of Reproduction 56:293-302.
Leupen SL, Besecke LM,
Levine JE 1997 Neuropeptide Y Y1 receptor stimulation is required for physiological
amplification of preovulatory luteinizing hormone (LH) surges. Endocrinology
138:2735-2739.
Top | Email Me | Dept. Home Page
The Laboratory for Human Biology Research is located within the Anthropology Department, and supports a range of projects investigating issues related to human health, growth and development, stress, reproductive ecology, energetics, and body composition. Current projects involve research in Samoa, Kenya, Bolivia, Siberia, and the Philippines. A primary mission of the laboratory is the development of minimally invasive, "field-friendly" methods for assessing biomarkers of health and development that can be used to facilitate population-level research in remote field settings. In recent research, whole blood samples have been collected from finger sticks and dried on filter paper in the field, and then brought back to the laboratory for analysis using modified ELISA protocols. Analysis of saliva and urine samples is also supported. The laboratory is committed to using these methods to facilitate collaborative, population-based research into the relationships between humans and their environments around the world.
Recent Publications:
McDade, T.W. (in press). Parent-offspring conflict and the cultural ecology of breastfeeding. Human Nature.
McDade, T.W., Stallings, J.F., Angold, A., Costello, E.J., Burleson, M., Cacioppo, J.T., Glaser, R. and C.M. Worthman (2000). Epstein-Barr virus antibodies in whole blood spots: A minimally-invasive method for assessing cell-mediated immunity. Psychosomatic Medicine 62: 560-568.
McDade, T.W., Stallings, J.F. and C.M. Worthman (2000). Culture change and stress in Western Samoan youth: Methodological issues in the cross-cultural study of stress and immune function. American Journal of Human Biology 12: 792-802.
McDade, T.W. and C.M. Worthman (1999). Evolutionary process and the ecology of human immune function. American Journal of Human Biology 11: 705-717.
McDade, T.W. and C.M. Worthman (1998). The weanling’s dilemma reconsidered: A biocultural analysis of breastfeeding ecology. Journal of Developmental and Behavioral Pediatrics 19(4): 286-299.
McDade, T.W., Angold, A., Costello, E.J., Stallings, J.F., and C.M. Worthman (1995). Physiologic bases of individual variation in pubertal timing and progression: A report from the Great Smoky Mountain Study. American Journal of Physical Anthropology Suppl 20: 148.
Top | Email Me | Dept. Home Page
Top
|
 |
We have found that concerted action of estradiol and progesterone regulates excitatory input to a major group of hippocampal output cells, the CA1 pyramidal cells. Hormone-induced changes in the density and number excitatory synaptic contacts on CA1 pyramidal cells are associated with increased sensitivity to excitatory synaptic input, enhanced synaptic plasticity, and greater susceptibility to seizure activity.
Thus, by regulating the physical substrates of information flow in the brain: dendrites, axons and the synapses that connect them, steroid hormones such as estradiol and progesterone may predispose neural circuitry to function differently in different hormonal states. Our aim is to understand how hormone-induced structural and functional plasticity regulates both normal an pathological brain function.
Recent Publications:
C. Woolley (1999). "Electrophysiological and cellular effects of estrogen on neuronal function." Crit. Rev. Neurobiol. 12: 1-20.
C. Woolley (1998). "Estrogen-mediated structural and functional and synaptic plasticity in the female rat hippocampus." Horm. Behav. 34: 140-148.
C. Woolley. N. G. Weiland, B. S. McEwen, and P. A. Schwartzkroin (1997).
"Estradiol increases the sensitivity of hippocampal CA1 pyramidal cells to NMDA
receptor-mediated synaptic input: Correlation with dendritic spine density" J.
Neurosci 17: 1848-1859 (1997).
The major focus of our research is to elucidate the molecular mechanisms of vulnerability to stress and to depression. One focus of our research is related to the recent characterization of the biological activity of a hypothalamic neuropeptide, prepro-TRH 178-199. This peptide inhibits ACTH and prolactin response to stress and shows anxiolytic and antidepressant activity in animal models of these behaviors. Ongoing work is aimed to clone the receptor for rat prepro-TRH 178-199 and its human analog, human prepro-TRH 158-183.
A second area of research is focused on the characterization of the inbred Wistar Kyoto (WKY) rat as a genetic animal model of depressive behavior and stress hyper-reactivity. This strain exhibits depressive-like behavior in numerous behavioral tests and exhibits hormonal abnormalities that are similar to those associated with depressive disorder in humans. These behavioral and hormonal differences between WKY and other inbred strains serve as phenotypes for quantitative trait loci (QTL) analysis, which we have recently started. Wistar Kyoto rats are also used to identify novel vulnerability genes that are expressed differentially in the amygdala and frontal cortex, brain regions involved in the psychopathology of human affective disorders, of ìdepressedî versus less ìdepressedî animals using the differential display RT-PCR technique.
We have been also investigating how environmental challenges in utero, such as fetal alcohol exposure, can lead to altered, and sexually dimorphic changes in the adult offspring neuroendocrine and immune functions. In addition to studying the biochemical mechanisms by which fetal alcohol exposure affects stress-responsiveness of the adult offspring, we are also studying its behavioral consequences. As early developmental, environmental insult seems to play a major role in depressed behavior in adulthood, and fetal alcohol exposure and prenatal stress share a common neuroendocrine ìimprintingî mechanism, this approach could provide important information on where and when the developing fetus acquires changes in the expression of specific genes that contribute to this vulnerability later in life.
Recent Publications:
Redei E, Li LF, Halasz I, McGivern RF, Aird F: Fast glucocorticoid feedback inhibition of ACTH secretion in the ovariectomized rat: Effect of chronic estrogen and progesterone. Neuroendocrinology, 60:113-123, 1994.
Redei E., Hilderbrand H., Aird F: Corticotropin Release-Inhibiting Factor is Prepro-Thyrotropin-Releasing Hormone-(178-199). Endocrinology, 136:3557-3563, 1995
Sinha P, Halasz I, Choi JF, McGivern RF, Redei E.: Maternal adrenalectomy eliminates a surge of plasma dehydroepiandrosterone in the mother and attenuates the prenatal testosterone surge in the male fetus. Endocrinology, 138:4792-4797, 1997
McGivern RF, Rittenhouse A.P, Aird F, Van de Kaar LD, Redei E: Inhibition of stress-induced neuroendocrine and behavioral responses in the rat by prepro-Thyrotropin Releasing Hormone 178-199. J. Neurosci.,17:4886-4894, 1997
Halasz I., Rittenhouse PA., Zorilla EP, Redei E: Sexually dimorphic effects of maternal adrenalectomy on hypothalamic corticotrophin releasing factor, glucocorticoid receptor and anterior pituitary POMC mRNA levels in rat neonates. Dev. Brain Res., 100:198-204, 1997
Engler D, Redei E, Kola I: The Corticotropin Release Inhibitory Factor Hypothesis: a review of the evidence for the existence of inhibitory as well as stimulatory hypophysiotropic regulation of adrenocorticotropin secretion and biosynthesis Endocr. Rev., 20:460-500, 1999
Top | Email Me | Dept. Home Page