Sunday, April 28, 2024
4/28/2024
Project Summary/ Abstract Sudden Infant Death Syndrome takes the lives of approximately 1,400 infants annually under the age of one and its etiology remains mostly unknown. Currently SIDS is explained via the triple risk model that proposes that SIDS occurs in a vulnerable infant during a critical developmental period when triggered by an external stressor, including failure of the neonate autoresuscitation reflex. Opioid receptors are expressed in brainstem regions that are integral for respiratory regulation and are known to contribute to respiratory dysfunction when homeostatic signaling is disrupted. Previous literature has identified an association between a mutation in the OPRM1 gene encoding mu opioid receptors (MORs) and SIDS cases, however, investigation of how this gene and perturbations in its SIDS associated variant of unknown significance modulates respiratory regulation are poorly understood. In the following aims, I will test the hypothesis that native OPRM1 function is integral to protective neonate respiratory reflexes and that an OPRM1 SIDS associated nucleotide variant negatively affects the neonatal autoresuscitation reflex. Aim 1: Does the loss of OPRM1 modulate the neonatal autoresuscitation reflex and respiratory dynamics following anoxic gas challenges? Aim 2: Determine the role of the 6 transmembrane (6TM) OPRM1 MOR variants in neonatal breathing and the protective autoresuscitation reflex. To test these aims, I will utilize genetic knockout (KO) mouse models to manipulate global OPRM1 expression and expression of specific classes of OPRM1 spice variants. For example, the OPRM1 exon 2 KO mouse model produces mice that do not express OPRM1 whereas the exon 11 and exon 1 KO mouse models only produce full length 7 transmembrane (TM) MOR variants or truncated 6TM variants, respectively. For functional characterization of respiratory dynamics, mice will be challenged with repeated sessions of hypercapnic anoxia to test their autoresuscitation reflex. For assessing network structure and cellular activation patterns, quantitative spatial transcriptomics will be applied to brainstem tissue of OPRM1 exon 2 KO, exon 11 KO, and exon 1 KO neonatal mice that have been challenged with bouts of sublethal hypercapnic anoxia. Determining the neuronal mechanisms of OPRM1 in the neonatal autoresuscitation reflex will provide crucial insight into risk factors contributing to congenital diseases including SIDS and NAS and may aid in the development of therapeutic interventions. This study will progress the field by elucidating the role MORs in respiratory regulation and dysfunction as well as its potential contribution as a risk factor to congenital diseases when expression is perturbed. This work will significantly aid in identification of the neuronal mechanisms and molecular targets involved in respiratory dysfunction underlying disease. The training plan and environment that accompany this proposal comprise of scientific and professional development courses, workshops, scientific seminars, and an environment enriched with technology at the forefront of the field which will provide a provident foundation for a transition to research independence.
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