A pilot project for high-throughput screening of genes involved in the neonate auto-resuscitation reflex to inform upon Sudden Infant Death Syndrome mechanisms
Authors: Patel Dipak , Ward Christopher , Ruiz Brandon , Garcia Mariana , Aissi Eunice , Ray Russell 
Published: May 2023

Sudden Infant Death Syndrome (SIDS) is defined as a diagnosis of exclusion in the sudden and unexpected passing of an infant, usually during sleep, with an unknown etiology. SIDS remains a leading cause of death in infants and is predominant in males (60%). A leading hypothesis is that many SIDS cases are driven by a failure in the autoresuscitation reflex. The autoresuscitation reflex is a series of gasps that occur, when an infant is experiencing an apnea and bradycardia due to sever hypoxic conditions (i.e. sleeping in a prone position), in order to revitalize cardiorespiratory function. Additionally, increasing number of SIDS cases are associated with genetic variants in key genes. However, it remains unclear what genes are critical to the development and function of the neonate auto-resuscitation reflex. In order to identify genes involved in neonate respiration and protective respiratory reflexes, we aim to build a phenotyping pipeline to screen large numbers of mouse mutants generated by the NIH Knock Out Mouse Project (KOMP). KOMP is a national and international consortium effort to knock out and phenotype every gene in the mouse genome. Based on preliminary KOMP data, as many as 10 percent of the mutated genes (≈ 2000) are expected to present perinatal viability phenotypes without any obvious structural abnormalities, offering potential SIDS models. To assay mutant mouse lines, we employ the neonate autoresuscitation assay, a high face-value assay to model face down or obstructed sleeping conditions thought to be faced by many SIDS infants. This assay consists of a series of anoxic challenges to induce apnea, followed by a return to room air rescue to facilitate autoresuscitation. However, the current manual approach for the assay is time consuming, highly variable, and low through-put creating a barrier to screening large numbers of genetic mutants. To address these barriers, we developed an automated approach to the autoresuscitation assay which is paired with a comprehensive cardio-respiratory data analysis software suite, both developed in the Ray lab. The automation allows for high-throughput, parallel screening of multiple mice while standardizing various parameters, such as exposure time and recovery parameters without the need for human observers, thus reducing variability. Utilizing this automated pipeline, we present results from a pilot study assaying 5 mouse lines with loss of function mutations in genes likely to be involved in protective respiratory reflexes. Here we report the successful identification of a previously untested gene involved autoresuscitation which displays a sex-specific vulnerability in the neonate autoresuscitation reflex. NIH/NHLBI R01 HLN161142-01 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.