Mechanisms of Down syndrome-associated swallowing dysfunction in mouse models

ABSTRACT Down syndrome (DS), a genetic disorder, is associated with accelerated aging and high levels of swallowing impairments (dysphagia). This is a critical concern given the increased survival of people with DS to older ages, and the association of dysphagia, aspiration pneumonia, and death. Although dysphagia is a prominent feature of DS, little is known about its age-related progression or the genetic mechanisms that underly its etiology. There are significant knowledge gaps in DS research regarding how the extra copy of the human 21st chromosome known to be present is driving DS phenotypes. The proposed research will address these gaps through a collaboration between two laboratories with substantial expertise in translational animal models of aging, DS, and dysphagia (Connor/Glass) and in the engineering of novel DS mouse models (Yu). The overarching goals of the proposed work are to quantify effects of aging on DS-related dysphagia and to resolve a current major uncertainty concerning the mechanisms underlying phenotypes in DS. There are two proposed aims: (Aim 1) To test the hypothesis that dysphagia is exacerbated by aging in mouse models of DS by quantifying swallowing function, tongue muscle alterations, changes in brainstem regions in mice of different ages, and by performing additional analyses at the molecular and phenotypic levels; and (Aim 2) To quantify the impacts of various components of a trisomy on swallowing function in DS in crucial behavioral and biological variables. We will pursue the objective of Aim 2 by generating and analyzing a number of the novel tailor-designed mouse models. This work is significant because it will define age-related changes in swallow function in mouse models of DS using an ecologically valid assay (videofluoroscopy) that is also used clinically in humans. Further, this work will introduce clarity regarding the impact of the critical elements of a trisomy on DS-related dysphagia by using new mouse models thereby allowing us to unravel molecular contributors to dysphagia in this context and to optimize translational precision. There are currently only limited compensatory treatments for DS-associated dysphagia, and thus there is an urgent need to enhance our mechanistic understanding of this clinical manifestation to support rational development of future therapeutic interventions. This proposal is in response to NOT-OD-20-025, for the NIH INCLUDE Project on Down syndrome research.