The premise of Project I is that an important subset of infants dying of SIDS have a neurobiological disorder whose elucidation requires the application of innovative quantitative tools directly in SIDS brain tissues, and for which there are potential biomarkers in readily accessible blood and/or platelets. Our key discovery to date Is that SIDS Is associated with neurotransmitter abnormalities In regions of the medulla oblongata that are critical for protective responses to homeostatic challenges during sleep. The most robust abnormalities are In serotonin (5-HT) and y-aminobutyric acid (GABA) parameters, as well as a deficiency of the 14-3-3-slgnal transduction family. These latter signaling proteins are known to play a role In central neurotransmitter and synaptic function. Including related to 5-HT. We now consider the basis of the putative medullary disorder in affected SIDS cases as a defect In a molecular Interaction network that affects 5-HT and GABA, as well as potentially other neurotransmitters as yet to be defined, and involves upstream abnormalities In 14-3-3.
In Specific Aim 1, we will determine whole genome expression profiles with transcriptome analysis of the raphe obscurus (RO) and Its Isolated 5-HT neurons (laser capture microscopy) of the medullary 5-HT system in SIDS cases compared to controls. Our approach will also uncover novel candidate genes with altered gene expression in SIDS, thereby providing insight Into the complete Interaction network at fault.
In Specific Aim 2, we will determine if there is a link in 5-HT and related pathology between caudal and rostral 5-HT domains of the brainstem and the key forebrain target of the rostral domain, i.e., the hippocampus. The elucidation of such a link in the same SIDS cases would reconfigure our understanding of the 5-HT related neuropathology of SIDS to a disorder broader than the brainstem only.
In Specific Aim 3, we will build upon our preliminary observations that serum 5-HT levels, which are dependent In large part upon platelet 5-HT metabolism, are elevated In a subset of SIDS Infants compared to controls. Indicating an Important lead, we believe, for eariy biomarker development directly In SIDS Infants. We will apply several methodologies for analysis of postmortem serum and platelets (known to contain important 5-HT-related receptors, transporter, and enzymes) in SIDS infants compared to controls, and correlate the findings with medullary parameters In the same SIDS cases. In all alms, we will analyze the effect upon outcomes of different clinicopathologic variables. Including male gender, prematurity, exposures to maternal cigarette smoke and SSRIs, and sleep position.
The relevance of Project I to SIDS Is that It has the potential to help determine effective treatments and biomarkers in Infants at risk based upon specific abnormal molecular pathways. It may also change our formulation of a neural SIDS subset as a 5-HT disorder that involves bralnstem-forebrain interconnections. There is no other laboratory in the world that is systematically analyzing SIDS brains and/or related biomarkers, and in parallel with animal modeling, as in Project I.
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