The sudden infant death syndrome (SIDS) is the leading cause of postneonatal infant mortality, with an overall incidence of 0.8/1000 live births. Its cause(s) is unknown. Based upon the investigators' brainstem studies in SIDS victims during the last grant cycle, they propose an expanded hypothesis concerning the role of the-ventral medulla, a region related to chemoreception, autonomic responses, respiratory drive, and thermoregulation, and the neurotransmitter, serotonin (5HT) in the pathogenesis of SIDS: SIDS, or a subset of SIDS, is due to a developmental abnormality in a ventral medullary network composed of rhombic lip-derived, serotonergic neurons, and this abnormality results in a failure of protective responses to life-threatening challenges (e.g., asphyxia, hypoxia, hypercapnia) during sleep.
In Specific Aims 1 -3, they will characterize the normal development of the 5-HT ventral medullary network in brain tissues across early life, the time-period of the pathogenesis of SIDS. They will utilize selected markers to 5-HT cells, terminals, receptor subtypes, and the synthetic enzyme, tryptophan hydroxylase, using tissue autoradiography, immunocytochemistry, and in situ hybridization in brain tissues from human embryos, fetuses, and infants. They will then determine how 5-HT development is abnormal in SIDS victims compared to age-matched controls with the same 5-HT markers.
In Specific Aim 4, they will establish which cell populations derive from the human rhombic lip using cellular and molecular markers to transcription factors implicated in rhombic lip derivation in animal studies, and will determine if the affected nuclei in the ventral medullary network in SIDS victims derive from this same embryonic anlage. They will determine if there is an abnormal number of neurons and reactive astrocytes (gliosis) in selected rhombic lip derived nuclei in SIDS victims. They predict that they will not find gliosis (scarring) in these nuclei suggesting a developmental, rather than degenerative, defect. The proposed studies should: substantiate a 5-HT defect in the ventral medulla of SIDS victims; provide insight into the normal development and the molecular and chemical anatomy of the human 5-HT ventral medullary network; and suggest clues about abnormal function in SIDS victims for testing in animal models, and for devising specific preventive strategies and diagnostic tests in human infants.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HD020991-16
Application #
6520803
Study Section
Special Emphasis Panel (ZRG1-BDCN-5 (01))
Program Officer
Willinger, Marian
Project Start
1992-09-01
Project End
2005-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
16
Fiscal Year
2002
Total Cost
$284,400
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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Broadbelt, Kevin G; Rivera, Keith D; Paterson, David S et al. (2012) Brainstem deficiency of the 14-3-3 regulator of serotonin synthesis: a proteomics analysis in the sudden infant death syndrome. Mol Cell Proteomics 11:M111.009530
Trachtenberg, Felicia L; Haas, Elisabeth A; Kinney, Hannah C et al. (2012) Risk factor changes for sudden infant death syndrome after initiation of Back-to-Sleep campaign. Pediatrics 129:630-8
Kinney, Hannah C; Broadbelt, Kevin G; Haynes, Robin L et al. (2011) The serotonergic anatomy of the developing human medulla oblongata: implications for pediatric disorders of homeostasis. J Chem Neuroanat 41:182-99
Broadbelt, Kevin G; Paterson, David S; Belliveau, Richard A et al. (2011) Decreased GABAA receptor binding in the medullary serotonergic system in the sudden infant death syndrome. J Neuropathol Exp Neurol 70:799-810
Cummings, Kevin J; Commons, Kathryn G; Hewitt, Julie C et al. (2011) Failed heart rate recovery at a critical age in 5-HT-deficient mice exposed to episodic anoxia: implications for SIDS. J Appl Physiol (1985) 111:825-33
Duncan, Jhodie R; Paterson, David S; Hoffman, Jill M et al. (2010) Brainstem serotonergic deficiency in sudden infant death syndrome. JAMA 303:430-7
Rognum, Ingvar Jon; Haynes, Robin L; Vege, Ashild et al. (2009) Interleukin-6 and the serotonergic system of the medulla oblongata in the sudden infant death syndrome. Acta Neuropathol 118:519-30
Kinney, Hannah C; Thach, Bradley T (2009) The sudden infant death syndrome. N Engl J Med 361:795-805

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