During early postnatal development the chemical phenotype (i.e. neurotransmitter, peptide, receptors and ionic channels) of neurons in brain areas involved in regulation of respiration and initiation of and recovery from apnea undergoes considerable change. Disruption of these developmental patterns as a result of an abnormal environmental condition (eg hypoxia) during gestation or early postnatal life might lead to neuronal dysfunction and consequently life threatening mechanisms responsible for the Sudden Infant Death Syndrome. Upper airway patency is essential for normal respiration and specific pathologic markers of SIDS indicate upper airway obstruction as a common mode of death in SIDS victims suggesting that an animal model demonstrating perturbations of upper airway development will provide new insights into the pathophysiology of SIDS. Molecular mechanisms that mediate tissue-specific regulation of cell phenotype during development are unknown. An excellent model for study is the disappearance of somatostatin (SOM) and its mRNA in the hypoglossal nucleus (nXII) during the first month in the rat. Acetylcholine and calcitonin gene-related peptide (CGRP) are present in nXII motoneurons throughout development. We hypothesize that SOM and CGRP gene expression in nXII motoneurons modulate acetylcholine receptor maturation in the genioglossus muscle.
The Specific Aims of this first study are: 1) To determine molecular factors affected by pre- and postnatal hypoxia that change temporal- and tissue-specific transcription of nXII motoneuron SOM and CGRP during early postnatal development. 2) To identify cis-elements and trans-acting protein factors that confer developmental regulation of the SOM gene in the hypoglossal neurons under conditions of normoxia and hypoxia. And, 3) to determine the trophic role of SOM in regulation of acetylcholine receptor subunit gene expression in genioglossus muscle during development in normoxia and hypoxia. Our preliminary data also indicate that gestational and postnatal hypoxia directly affects electrophysiologic excitability of nXII motoneurons themselves. We hypothesize that this mechanism is due to alterations in the ionic channels present in the membranes of these neurons.
The Specific Aims of the second study are: 1) To determine biophysical membrane properties of nXII motoneurons at different postnatal ages and under conditions of prexisiting normoxia or hypoxia. And, 2) to determine which membrane ionic pathways are affected by rearing under conditions of pre- and postnatal hypoxia.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD028948-03
Application #
3330465
Study Section
Special Emphasis Panel (SRC (SI))
Project Start
1991-09-30
Project End
1994-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Millhorn, D E; Raymond, R; Conforti, L et al. (1997) Regulation of gene expression for tyrosine hydroxylase in oxygen sensitive cells by hypoxia. Kidney Int 51:527-35
Millhorn, D E; Conforti, L; Beitner-Johnson, D et al. (1996) Regulation of ionic conductances and gene expression by hypoxia in an oxygen sensitive cell line. Adv Exp Med Biol 410:135-42
Zhu, W H; Conforti, L; Czyzyk-Krzeska, M F et al. (1996) Membrane depolarization in PC-12 cells during hypoxia is regulated by an O2-sensitive K+ current. Am J Physiol 271:C658-65
Norris, M L; Millhorn, D E (1995) Hypoxia-induced protein binding to O2-responsive sequences on the tyrosine hydroxylase gene. J Biol Chem 270:23774-9
Czyzyk-Krzeska, M F; Furnari, B A; Lawson, E E et al. (1994) Hypoxia increases rate of transcription and stability of tyrosine hydroxylase mRNA in pheochromocytoma (PC12) cells. J Biol Chem 269:760-4
White, L D; Lawson, E E; Millhorn, D E (1994) Ontogeny of the O2-sensitive pathway in medulla oblongata of postnatal rat. Respir Physiol 98:123-35
Erickson, J T; Millhorn, D E (1994) Hypoxia and electrical stimulation of the carotid sinus nerve induce Fos-like immunoreactivity within catecholaminergic and serotoninergic neurons of the rat brainstem. J Comp Neurol 348:161-82
Bayliss, D A; Viana, F; Kanter, R K et al. (1994) Early postnatal development of thyrotropin-releasing hormone (TRH) expression, TRH receptor binding, and TRH responses in neurons of rat brainstem. J Neurosci 14:821-33
Kanter, R K; Erickson, J T; Millhorn, D E (1994) Activation of the c-fos gene in prodynorphin- and proenkephalin-expressing cells of nucleus tractus solitarius after seizures. Exp Neurol 129:290-8
Millhorn, D E; Czyzyk-Krzeska, M; Bayliss, D A et al. (1993) Regulation of gene expression by hypoxia. Sleep 16:S44-8

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