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Grant Abstract: Pathology, Developmental Origins, and Prevention of Pediatric Dysphagia

Grant Number: 5P01HD083157-03S1
PI Name: Lamantia
Project Title: Pathology, Developmental Origins, and Prevention of Pediatric Dysphagia

Abstract: Many developmental disorders, including 22q11.2 deletion syndrome (DiGeorge syndrome) compromise orofacial development, which leads to difficulties in feeding and swallowing (dysphagia). In our current P01 project “Pathology, Developmental Originis, and Prevention of Pediatric Dysphagia”, we have stab lished that we can use the mouse model of 22q11.2 Delection Syndrome (referred to as LgDel) as a model of pediatric dysphagia to identify how developmental processes that impact feeding and swallowing may be disrupted. Using this model we have also identified disruptions in the development, morphology, and function of several key cranial nerves and brainstem nuclei that are central to proper feeding and swallowing. In a separate project, we identified a potential molecular source of developmental and functional impairment in crebal cortical development in these mice: the reuced ability of LgDel neurons to metabolize reactive oxygen (ROS). Increased ROS in LgDel neurons leads to impaired axonal and dendritic growth, and multiple signs of cellular damage and stress including reduced content of ribosomes and miotchondria with sollen, distended cristae. We recently found that treatment of LgDel pups, starting at birth, with an over-the-counter antioxidant dietary supplement (N-acetyl-cysteine) leads to morpholoical rescue of excitatory neurons. We hypothesize that similar ROS-mediated cysfunction may be a key mediator of the cranial nerve and brainstem anomalies that we identified itn the LgDel mouse, and that treatment with a dietary supplement that reduces oxidative stress may improve dysphagia-related outcomes. We proposed that a similar dietary supplement of an anti-oxidant may rescue aspects of impaired morphology and function fo the cranial nerves and brainstem nuclei that contribute to dysphagia.

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