# Central & Peripheral Mechanisms of Respiratory & Autonomic Control Dysfunction in a Novel Model of SIDS: Predictive Biomarkers and the Role of the Extracellular Matrix

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $571,213

## Abstract

Project Summary
The Triple Risk Model describes SIDS occurrences when an intrinsically vulnerable infant experiences an
exogenous insult resulting in a chronically hypoxic/hypercapnic environment particularly during a critical
developmental period. SIDS pathophysiology includes evidence of chronic hypoxia exposure, brainstem gliosis
and serotonergic abnormalities, as well as respiratory/autonomic dysfunction and carotid body abnormalities.
Although animal models have been instrumental in advancing our understanding of SIDS, the lack of models
that recapitulate the hallmark features has hindered our ability to confirm SIDS pathophysiology and resolve
the major hypothetical/proposed features. We resolved this hurdle after discovering a rat model that closely
simulates postnatal hypoxia component of SIDS as an exogenous stressor in a vulnerable neonate. In this
model, prolonged/sustained (days) hypoxia exposure during a uniquely critical period of postnatal development
results in spontaneous unexplained death several days later. Importantly, in both published and preliminary
studies (this proposal) the model recapitulates ALL of the aforementioned SIDS features. Here, using our novel
model, we propose the novel hypothesis that the hallmark brainstem abnormalities (microglia and 5-HT) in
SIDS is in response to chronic disruption of carotid body afferent inputs into the brainstem. We propose that
these disrupted inputs over several days are sufficient to elicit a localized brainstem microglial response (as
seen in SIDS), ultimately leading to the fatal abnormalities in brainstem neurochemistry in key
respiratory/autonomic control regions. A particularly novel component of our proposal is the discovery of a
microglial inhibitor, which prevents the adverse effects of hypoxia exposure, thus for the first time in any
setting, we may be on the path to a preventative measure against SIDS. We also propose that aberrant
expression of several components of the extracellular matrix may be a new central (brainstem) and peripheral
(carotid body) pathophysiological mechanism in SIDS. Finally, given the compelling similarities in our model
with SIDS cases, we are poised to assess serum and urine biomarkers for identifiers of at-risk infants and
predictors of later mortality. Overall, this proposal will: 1) be fundamental to our understanding of respiratory
and autonomic dysfunction associated with SIDS, 2) provide a mechanistic perspective on the root cause of
the common brainstem abnormalities, 3) discover potentially new SIDS pathophysiology (per the requirements
of the NOSI, and 4) reveal a glimmer of hope at a prophylactic treatment toward SIDS prevention.

## Key facts

- **NIH application ID:** 10800086
- **Project number:** 1R01HD111415-01A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Peter MacFarlane
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $571,213
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10800086

## Citation

> US National Institutes of Health, RePORTER application 10800086, Central & Peripheral Mechanisms of Respiratory & Autonomic Control Dysfunction in a Novel Model of SIDS: Predictive Biomarkers and the Role of the Extracellular Matrix (1R01HD111415-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10800086. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*