P01HD213500005   MEYERS, DEAN A          FETAL NEUROENDOCRINOLOGY, PARTURITION
-PROJECT NUMBER......5 P01 HD21350-07     SUB: 0005
                                     FY  94    MEYERS, DEAN A
IRG/INTRAMURAL UNIT..SRC                       CORNELL UNIVERSITY
AWARD AMOUNT.........   $132,516
                                               ITHACA, NY  14853-6401
PERFORMING ORGANIZATION: CORNELL UNIVERSITY ITHACA
TITLE   FETAL NEUROENDOCRINOLOGY, PARTURITION AND THE MYOMETRIUM
  SUB TITLE MOLECULAR NEUROENDOCRINOLOGY OF THE FETAL HYPOTHALAMUS

ABSTRACT:

Molecular and cellular events within AVP and CRH neurons in the fetal PVN
that regulate the hypothalamo-hypophyseal-adrenal axis (HHAA) during the
final third of pregnancy are poorly defined.  In sheep, fetal adrenal
maturation and subsequent cortisol secretion is necessary for parturition
and maturation of organs critical for neonatal survival.  In years 01-05
we combined whole animal experimental paradigms and molecular techniques
to dissect critical mechanisms that regulate the HHAA in sheep in the
last 30-40 days gestation (dGA).  By specific lesions of, or
dexamethasone implants adjacent to the fetal PVN we demonstrated the
importance of the fetal PVN in regulating maturation of the fetal HHAA
and parturition.

We propose two hypotheses: 1) gene expression and activity within AVP and
CRH neurons of the fetal PVN increases immediately preceding the
preparturient increase in adrenocortical function and; 2) glucocorticoid
negative feedback efficacy mediated by altered expression of the
glucocorticoid receptor within the fetal PVN changes at approximately 125
dGA allowing sustained expression of AVP and CRH genes despite increasing
endogenous fetal cortisol secretion.

We have six Specific Aims to test our hypotheses.  We will examine:

1. Ontogenic changes from 100-145 dGA in: a) c-fos expression as an index
of neuronal activity within AVP and CRH neurons of the fetal PVN; b) AVP
and CRH gene expression within the parvocellular fetal PVN;

2. Changes in response to fetal hypoxemia in a) c-fos as an index of
neuronal activity within AVP and CRH fetal PVN neurons; b) AVP and CRH
gene expression in the parvocellular fetal PVN; c) POMC expression in
fetal anterior pituitary corticotropes;

3. Changes in response to bilateral fetal adrenalectomy during the period
100-135 dGA in: a) c-fos expression as an index of neuronal activity
within the AVP and CRH fetal PVN parvocellular component; b) AVP and CRH
gene expression within fetal PVN parvocellular neurons; c) POMC gene
expression within fetal anterior pituitary corticotropes;
4. Ontogenic changes from 100-145 dGA in GR expression in: a) fetal AVP
and CRH neurons; b) fetal anterior pituitary corticotropes;

5. Effects of fetal adrenalectomy and physiological glucocorticoid
replacement on GR expression from 100-135 dGA in: a) fetal AVP and CRH
neurons; b) fetal anterior pituitary corticotropes;

6. Changes in GR expression in response to fetal hypoxemia in: a) fetal
AVP and CRH neurons; b) fetal anterior pituitary corticotropes.

These studies examine the maturation and regulation of the fetal PVN and
anterior pituitary utilizing a combined molecular, cellular, and in vivo
approach.  They continue and extend knowledge of the critical role of the
fetal PVN in fetal adrenal maturation and parturition that we have
provided in years 01-05.

CRISP INDEXING TERMS FROM CRISP THESAURUS:
04782310P   paraventricular nucleus
10256954P   hormone regulation /control mechanism
12568024P   gene expression
20543064P   neuroendocrine system
23342812P   corticotropin releasing factor
23346375P   arginine vasopressin
24017877P   embryo /fetus
25732440P   corticosteroid receptor
00596844S   glucocorticoid
00596967S   cortisol
06175328S   cerebral ischemia /hypoxia
10257964S   steroid hormone biosynthesis
12575500S   protooncogene
20473601S   neuron
20536900S   developmental neurobiology
23341560S   pituitary adrenal axis
23342074S   hypothalamic pituitary axis
23345463S   proopiomelanocortin
23350113S   pituitary gland
24008114S   pregnancy
24017912S   gestational age
25730400S   receptor expression
26046846S   embryo /fetus hypoxia
40000173S   embryogenesis
00621836T   adrenalectomy
01821920T   sheep
10258739T   hormone therapy
15542150T   immunocytochemistry
15552261T   radioimmunoassay
21017950T   in situ hybridization
25386642T   autoradiography
40000271T   northern blotting