The cause of the sudden infant death syndrome (SIDS), which claims approximately 7000 lives a year is unknown. We are investigating the idea SIDS is due to a subtle brain abnormality that is manifested as a failure to arouse from a life-threatening episode during sleep in a vulnerable developmental period. In the next grant period, we propose to focus upon two major leads which have emerged from our research in SIDS brains in the previous grant period, and which we believe are directly relevant to the arousal deficit hypothesis. These leads are: 1) delayed central nervous system (CNS) myelination in SIDS victims; and 2) a potential vulnerability in the development of the nicotinic (NIC) cholinergic system during the SIDS time-frame. We have targeted the nicotinic cholinergic system because it has the potential to inter-relate several themes in SIDS, including maternal cigarette smoking during pregnancy as a major risk factor for SIDS, delayed myelination, and aberrant development in a key transmitter system involved in arousal during a critical period.
SPECIFIC AIM 1 will test the hypothesis that the subtle delay in CNS myelination in SIDS defined by us in an anatomic study during the last grant period is due to a failure of glial progenitor cells to differentiate into mature, myelin-forming oligodendrocytes at the proper time. Over a 5-year period, we propose to analyze various parameters of oligodendrocyte differentiation and myelin formation with biochemical immunocytochemical, and ultrastructural tools.
SPECIFIC AIM 2 will test the hypothesis that the development of the nicotinic cholinergic system is abnormal in SIDS in forebrain regions critical to arousal. We will compare the developmental profile of nicotinic receptor binding in the same SIDS and control brains in which myelin is analyzed. We will focus upon 7 limbic-paralimbic regions in which we detected subtle hypomyelination in the previous anatomic study, and for which acetylcholine is a key transmitter system. We will also analyze muscarinic and serotoninergic binding to test the specificity of the putative transmitter changes to the nicotinic system. Receptor binding will be measured by tissue autoradiographic methods in sections according to protocols established by us in the last grant period. Integration of the myelin and receptor data, obtained in the same brains, should provide important insight into the relationship between the two developmental processes postulated by us to underlie the risk for SIDS: forebrain myelination and nicotinic cholinergic maturation.
| Haynes, Robin L; Frelinger 3rd, Andrew L; Giles, Emma K et al. (2017) High serum serotonin in sudden infant death syndrome. Proc Natl Acad Sci U S A 114:7695-7700 |
| Edlow, Brian L; Haynes, Robin L; Takahashi, Emi et al. (2013) Disconnection of the ascending arousal system in traumatic coma. J Neuropathol Exp Neurol 72:505-23 |
| Randall, Bradley B; Paterson, David S; Haas, Elisabeth A et al. (2013) Potential asphyxia and brainstem abnormalities in sudden and unexpected death in infants. Pediatrics 132:e1616-25 |
| Kinney, Hannah C; McDonald, Anna G; Minter, Megan E et al. (2013) Witnessed sleep-related seizure and sudden unexpected death in infancy: a case report. Forensic Sci Med Pathol 9:418-21 |
| Paterson, David S (2013) Serotonin gene variants are unlikely to play a significant role in the pathogenesis of the sudden infant death syndrome. Respir Physiol Neurobiol 189:301-14 |
| Haynes, Robin L; van Leyen, Klaus (2013) 12/15-lipoxygenase expression is increased in oligodendrocytes and microglia of periventricular leukomalacia. Dev Neurosci 35:140-54 |
| Cummings, Kevin J; Commons, Kathryn G; Trachtenberg, Felicia L et al. (2013) Caffeine improves the ability of serotonin-deficient (Pet-1-/-) mice to survive episodic asphyxia. Pediatr Res 73:38-45 |
| Serang, Oliver; Froehlich, John W; Muntel, Jan et al. (2013) SweetSEQer, simple de novo filtering and annotation of glycoconjugate mass spectra. Mol Cell Proteomics 12:1735-40 |
| McDowell, Gary S; Gaun, Aleksandr; Steen, Hanno (2013) iFASP: combining isobaric mass tagging with filter-aided sample preparation. J Proteome Res 12:3809-12 |
| 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 |
Showing the most recent 10 out of 49 publications
