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1.
Description of the Department
For education of medical students, the department is in charge of Physiology, mainly in the field of general physiology, and physiology in the muscle and nerve, endocrine, respiratory, digestive, and reproductive systems. For education of master-degree students, we provide courses in general physiology. And for education of doctorate-degree students, we are in charge of Environment and Biological Response Course, Human Environment Medical Engineering, Division of Medicine and Engineering Science (Arita) and a course in Bioregulation, Division of Medicine (Saigusa).
2.
Profile of the Faculty Members (Area of Research)
lJun ARITA, Professor:
Neuroendocrine actions of estrogen and its action mechanism
Takeshi SAIGUSA, Assistant Professor:
The role of brain angiotensin in cardiovascular regulation
Maho ISHIDA, Research Associate:
Involvement of estrogen-receptors and intercellular interaction in the proliferation regulation mechanism of estrogen-responsive cells
Tetsuo MITSUI, Research Associate:
The mechanism of antimitogenic action of estrogen
Michi TANAKA, Administrative Official
3.
Research Activities
General Description: Estrogen, an ovarian hormone, not only plays an important role in the performance of the female reproductive function, but it also greatly influences unrelated tissues such as bones, veins, and the brain. Our first theme of research is estrogen's proliferative action in the uterus, mammary gland, and anterior pituitary gland, which are the representative target tissues of estrogen. Meanwhile, we also conduct research to unravel the action of angiotensin in the center for circulation in the medulla oblongata, apart from estrogen-related studies.
Theme 1:
1) Since it is difficult to prove the proliferative action of estrogen in primary cultures of the uterus and mammary gland, most conventional research has used cell lines instead. We established an experimental system using primary cultures, which is essential to examine estrogen's proliferative action and its mechanism. The growth of the prolactin-producing cells lactotrophs is regulated by three extracellular regulators, estrogen originated in the ovary, dopamine originated in the hypothalamus, and the growth factors originated in the anterior pituitary gland itself. We investigated the intracellular signal transduction system which mediates these three regulators using primary cultures and showed that estrogen modulates the cell growth of lactotrophs via estrogen-receptors, the hypothalamus factor does same via cyclic AMP, and growth factors including insulin-like growth factor I (IGF-I) do same via mitogen-activated protein kinase (MAPK). We also proved that cyclic AMP and MAPK are essential for the proliferative action of estrogen, and contrarily, estrogen-receptors are essential for the proliferative action of cyclic AMP and MAPK. These results reveal that the growth regulation of estrogen-responsive cells is a very complex mechanism which requires many interactions between intracellular signaling pathways.
.2) Hypothalamic hormones including dopamine regulate critical functions
of pituitary cells via the cAMP-protein kinase A (PKA) pathway. The PKA-downstream
transcription factor cAMP response element-binding protein (CREB) is known
as an integrating molecule that is also activated by many other protein
kinase pathways. We investigated the involvement of CREB in the regulation
of cell proliferation and the prolactin promoter activity of lactotrophs.
Dopamine inhibited CRE-mediated transcription and CREB phosphorylation
in lactotrophs. Expression of a dominant-negative form of CREB (MCREB)
by recombinant adenovirus-mediated gene delivery inhibited cAMP-induced
prolactin promoter activity and lactotroph proliferation. MCREB expression
also inhibited IGF-1-induced lactotroph proliferation. These results suggest
that CREB is involved in the regulation of functions in normal lactotrophs
and that dopamine inhibition of these lactotroph functions is due to inhibition
of the cAMP-PKA-CREB pathway.
3) It is known that estrogen promotes cell growth in the various estrogen-responsive
cells, but it also inhibits growth of some tissues such as vascular smooth
muscle. We discovered that in lactotrophs estrogen unexpectedly inhibits
the growth by IGF-I, while it also promotes cell growth by serum and cyclic
AMP, suggesting that estrogen's antimitogenic action is mitogen-dependent.
This estrogen's culture-condition-dependent antimitogenic action was observed
in not only lactotrophs but also in MCF-7, a typical breast cancer cell
line. These results suggest that not only the stimulatory mechanism but
also the inhibitory mechanism are inherent within the estrogen's growth
regulation in the estrogen-responsive cells. In addition, we have generated
transgenic rats expressing green fluorescent protein (GFP) under the control
of the prolactin promoter and succeeded in enriching lactotrophs by collecting
GFP-expressing pituitary cells with fluorescence-activated cell sorting
from these rats. Using enriched lactotrophs, we have shown that the antimitogenic
and mitogenic actions of estrogen on lactotrophs do not require paracrine
signals from other pituitary cell types and that estrogen directly alters
lactotroph proliferation.
Theme 2: Angiotensin (Ang) is one of the hormones that regulate blood pressure and body fluid and electrolyte balances. In addition to its roles as a circulating hormone, Ang also participates in local regulation of many organs, including the heart, kidney, and brain. Taking electrophisiological approaches, we have investigated the role of brain Ang in the control of sympathetic nerve activity. We found that sympathetic baroreflex was tonically affected by endogenous Ang at the level of the ventrolateral medulla (VLM), which is one of the integrative sites of the sympathetic nerve activity. Consequently, we investigated the action of Ang to the sympathetic premotor neurons in the VLM to clarify the neuronal mechanism of the Ang-induced sympathetic baroreflex modulation, and found that Ang altered not only the baseline activities of the sympathetic premotor neurons, but also their phasic responses evoked by slow and rapid changes in blood pressure.
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