Inflammatory stressors in serotonergic brainstem dysfunction and sids

Active Project Grant Awarded Last action

Award ID
R01HD107060
Recipient
Awarding agency
Obligated
$5,869,082

Award facts

Completion date 89% complete
Place of performance
Boston, MA 02115, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
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-1SS, 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.

Transactions

Action Obligated Date
Amendment $723,154
Amendment $723,152
Amendment $65,044
Amendment $65,044
Amendment $650,415
Amendment $650,415
Amendment $650,415
Amendment $780,481
Amendment $780,481
Original award $780,481

Subawards

Subrecipient Amount Awarded
University Of California, San Diego Elisabeth Haas, MPH Is an employee of the University of California San Diego and badged volunteer with the County Medical Examiner; she will serve as the SIDS… $155,226
President And Fellows Of Harvard College This research study will dovetail the evaluation of human postmortem Sudden Infant Death Syndrome (SIDS) cases with genetically engineered mouse models amenable… $257,510
Veterans Education And Research Association Of Northern New England, Inc. Dr. Leiter’s team is crucial to the success of this project examining the timing of hypoxic exposure and the generation of neuroinflammation in either a… $67,069

Quick answers

Who received award R01HD107060?

R01HD107060 was awarded to The Children's Hospital Corporation by National Institute of Child Health and Human Development (National Institutes of Health) on July 1, 2023.

How much is award R01HD107060 worth?

$5,869,082 has been obligated on R01HD107060.

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