Document text
Principal Investigator: ROBIN Lynn HAYNES
Organization: BOSTON CHILDREN'S HOSPITAL
Fiscal Year: 2024
Award: $715,459
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Project Summary
Sudden infant death syndrome (SIDS) remains the leading cause of post-neonatal mortality in the U.S.– an
unchanging and devastating fact despite implementation of safe sleep practices (extrinsic risk reduction).
Addressing this 21st century health crisis now requires discovery of intrinsic biological vulnerabilities and
plausible molecular pathways that might lead to biomarkers and preventative interventions. In multiple
independent SIDS tissue datasets, serotonergic (5-HTergic) abnormalities in the brainstem were consistently
identified; in animal models of reduced brainstem 5-HTergic activity, compromised autoresuscitation (AR) was
observed – the ability of mouse pups to recover from cycles of asphyxial apneas and bradycardia (resembling
the cycles of apnea and bradycardia observed in some SIDS cases) was significantly diminished. Such 5-
HTergic system dysfunction, as an intrinsic vulnerability, may be caused or exacerbated by extrinsic stressors
such as pre- and/or postnatal hypoxia (e.g., placental insufficiency, parental smoking) and/or antemortem
infections. Hypoxia and infection are each risk factors for SIDS and can increase neuroinflammation, which can
impair AR. Notable new findings in some SIDS cases as compared to controls are elevations of the
neuroinflammatory markers IL-1β, IL-2, IL-4, IL-17, and GM-CSF and/or in neopterin (a marker of Th1
(proinflammatory) cellular activation) in the cerebrospinal fluid. We postulate that neuroinflammation,
triggered by hypoxia and/or antemortem infections (bacterial or viral), interact to create a vulnerable 5-
HTergic system, reduce AR effectiveness, and increase the risk for sudden death, and may underlie
some SIDS cases. We propose: 1) To quantitate inflammatory mediators within SIDS brains and determine
whether a profile of mediators associates with 5-HTergic brainstem abnormalities. We will test the hypothesis
that specific inflammatory profiles associate with low 5-HT1A and 5-HT2A receptor binding and low 5-HT levels. 2)
To map at single-cell resolution, differences in gene expression profiles and overall cell-type composition/states
of brainstem tissue across SIDS cases (the SIDS subsets identified through Aim 1) and controls. We hypothesize
that SIDS subsets will be distinguished by specific inflammatory profiles in glia, neurons, and/or endothelial cells,
and gene expression differences will identify novel, previously unrecognized SIDS-related pathways for
mechanistic testing in cell and animal models. 3) Assess the interaction between chronic intermittent hypoxia
(gestational to P8) and postnatal antemortem infection on molecular, cellular, inflammatory, and physiological
readouts, including the autoresuscitation response (AR). We will test the hypothesis that the combined effects
of antemortem hypoxia and infection interact to create greater neuroinflammation, more severe 5-HTergic
deficits, and increased likelihood of AR failure, compared to either hypoxia or infection alone. SIDS research
must address the missing mechanistic links between risk factors and postmortem pathology to develop life-
saving interventions.
Terms: <5-HT><5-HT pathway><5-HT system><5-HT(2A) Receptor><5-HT2A Receptor><5-Hydroxytryptamine><5HT><Address><Affect><Age><Animal Model><Animal Models and Related Studies><Apnea><Autopsy><B cell growth factor><B-Cell Differentiation Factor-1><B-Cell Growth Factor-1><B-Cell Growth Factor-I><B-Cell Proliferating Factor><B-Cell Stimulating Factor><B-Cell Stimulating Factor-1><B-Cell Stimulation Factor-1><B-Cell Stimulatory Factor-1><BCDF-1><BCGF><BCGF-1><BCSF 1><BSF-1><BSF1><Back to Sleep><Beta Proprotein Interleukin 1><Binetrakin><Biologic Models><Biological><Biological Markers><Biological Models><Body Tissues><Bradycardia><Brain><Brain Nervous System><Brain Stem><Brainstem><Breathing><CTLA-8><CTLA-8 Gene><CTLA8><CTLA8 Gene><Cause of Death><Cell Body><Cell model><Cells><Cellular model><Cerebrospinal Fluid><Chemotactic Cytokines><Chronic><Cluster Analyses><Cluster Analysis><Co-Stimulator><Costimulator><Cot Death><Crib Death><Cytosine Polynucleotides><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Antigen 8 Gene><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8 Gene><Data Set><Defect><Detection><Dinoprostone><Dysfunction><Effectiveness><Embryo><Embryonic><Encephalon><Endothelial Cells><Engineering><Enteramine><Environmental Factor><Environmental Risk Factor><Epidermal Thymocyte Activating Factor><Event><Expression Signature><Failure><Functional disorder><GM-CSF><Gene Expression><Gene Expression Profile><Gestation><Glia><Glial Cells><Granulocyte-Macrophage Colony-Stimulating Factor><Health><Hippophaine><Histamine-Producing Cell-Stimulating Factor><Histology><Homologous Chemotactic Cytokines><Human><Hypoxia><Hypoxic><IL-1 beta><IL-1 β><IL-1-b><IL-17><IL-17 Gene><IL-17A><IL-17A Gene><IL-1β><IL-2><IL-4><IL1-Beta><IL1-β><IL17><IL17 Protein><IL17 gene><IL17A><IL17A Gene><IL1B Protein><IL1F2><IL1β><IL2 Protein><IL4 Protein><Impairment><In Situ Hybridization><Incidence><Infant><Infant Mortality><Infant Mortality Total><Infection><Inflammation><Inflammation Mediators><Inflammatory><Injections><Intercrines><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8) Gene><Interleukin 17 Precursor><Interleukin 17 Precursor Gene><Interleukin 1beta><Interleukin 2><Interleukin 2 Precursor><Interleukin II><Interleukin-1 beta><Interleukin-17><Interleukin-1β><Interleukin-2><Interleukin-4><Interleukin-4 Precursor><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Intervention><Intervention Strategies><Kolliker's reticulum><Kynurenine><Life><Link><Lipopolysaccharides><Lymphocyte Mitogenic Factor><Lymphocyte Stimulatory Factor 1><MCGF-2><Maps><Mast Cell Growth Factor-2><Mediator><Mice><Mice Mammals><Mitogenic Factor><Model System><Modern Man><Molecular><Molgramostin><Murine><Mus><Neopterin><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neuroglia><Neuroglial Cells><Neurons><Non-Polyadenylated RNA><Non-neuronal cell><Nonneuronal cell><O element><O2 element><Oxygen><Oxygen Deficiency><PGE2><PGE2 alpha><PGE2alpha><Pathology><Pathway interactions><Pattern><Physiologic><Physiological><Physiopathology><Placental Insufficiency><Poly C><Poly I-C><Polycytidylic Acids><Polyinosinic-Polycytidylic Acid><Pregnancy><Preinterleukin 1 Beta><Preventative intervention><Preventative strategy><Prevention><Prevention strategy><Preventive strategy><Prostaglandin E2><Prostaglandin E2 alpha><Prostaglandin E2alpha><Protocol><Protocols documentation><RNA><RNA Gene Products><Recovery><Reflex><Reflex action><Research><Resolution><Respiratory Aspiration><Respiratory Inspiration><Ribonucleic Acid><Risk><Risk Factors><Risk Reduction><SIDS><SIS cytokines><Safe Sleep><Safe to Sleep Campaign><Saline><Saline Solution><Sampling><Serotonergic System><Serotonin><Serotonin 2A Receptor><Serotonin Receptor 5-HT2A><Single-Nucleus Sequencing><Smoking><Source><Stress><Sudden Death><Sudden Infant Death><Sudden Unexpected Infant Death><Sudden infant death syndrome><T cell growth factor><T-Cell Growth Factor><T-Cell Growth Factor 2><T-Cell Stimulating Factor><TC-GM-CSF><Testing><Thymocyte Stimulating Factor><Tissues><Tumor-Cell Human GM Colony-Stimulating Factor><Validation><Viral><Work><ages><bio-markers><biologic><biologic marker><biomarker><brain tissue><cell type><cerebral spinal fluid><chemoattractant cytokine><chemokine><cohort><compare to control><comparison control><cytokine><death among infants><death in first year of life><death in infancy><death in infants><environmental risk><experience><gene expression pattern><gene expression signature><granulocyte macrophage colony stimulating factor><homopolymer 5'-Cytidylic acid><human tissue><in situ Hybridization Genetics><in situ Hybridization Staining Method><in vivo><infant death><infant demise><infantile death><inflammatory mediator><insight><inspiration><intervention effect><intervention for prevention><interventional strategy><model of animal><mortality in infants><necropsy><nerve cement><neural inflammation><neuroinflammation><neuroinflammatory><neuronal><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><normoxia><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pathophysiology><pathway><poly I:C><poly IC><poly(I:C)><post-natal intermittent hypoxia><postmortem><postnatal><postneonatal death><postneonatal infant death><postneonatal infant mortality><postneonatal mortality><prevent><preventing><prevention intervention><preventional intervention strategy><preventive intervention><pup><receptor binding><receptor bound><reduce risk><reduce risks><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing the risk><resolutions><response><risk-reducing><sNuc-Seq><serotonergic pathway><serotonin pathway><serotonin system><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><snRNA sequencing><snRNA-seq><spinal fluid><stressor><success><transcriptional profile><transcriptional signature><validations>