Yu, Eugene PHD

Developmental delays and intellectual disabilities are common co-occurring conditions in Down syndrome, which is associated with an extra copy of human chromosome 21, and our proposed research aims to identify new target genes with therapeutic potential for improving cognitive function and thus the quality of life in people afflicted with this chromosomal alteration. These genes will be identified through the use of phenotype-based tests in mouse models tailor-made to facilitate genetic dissection of Down syndrome, and these models will be developed with the aid of CRISPR genome engineering technology. We will also test whether the characteristic features of Down syndrome are impacted by the gene-dosage-independent effects of trisomy 21, such as through alterations in the nuclear architecture, which could help to transform the current paradigm of understanding for Down syndrome-associated cognitive deficits.

Down syndrome (DS) is associated with difficulties in speech, breathing, and swallowing, but the reasons for these difficulties remain unknown. Mouse models can be used to study the potential mechanisms for impairment of these critical activities. The proposed research will study how aging impacts swallowing function in adult mouse models of DS and will generate new mouse models to reveal the molecular underpinnings of swallowing dysfunction associated with DS, thereby expanding knowledge of this important clinical manifestation.

In this supplement/revision application, we are focused on three important co-occurring clinical phenotypes in Down syndrome (DS): age-related immune system alterations, age-dependent hearing loss, and age-dependent cognitive decline (independently of Alzheimer’s disease). Our long-term objectives are to ask whether measuring biological and molecular markers of aging in chromosomally engineered mouse models of DS can help to answer (i) what are the genes on chromosome 21 that cause early aging epigenetic aging in DS? (ii) what are the genes on this chromosome that cause early biological aging in DS (iii) does epigenetic aging influence biological aging? and (iv) do early epigenetic and biological aging contribute to the above listed medical conditions? To lay a foundation for achieving these goals, in our 2-year aims, we seek to determine whether the duplications of two chromosome 21 orthologous chromosomal regions in our mouse models affects epigenetic/transcriptomic/biological aging, thus contributing to the rate of development of the co-occurring conditions in DS, with implications for these same common age-related conditions in the general population.

Given the major importance of the COVID-19 pandemic, with >3M cases and >130K deaths in the USA alone, and potential vulnerability of people with Down syndrome (DS; trisomy 21), we propose here to elucidate biological, genetic and epigenetic factors that can influence the response to SARS-CoV-2 in people with DS. We will map DNA methylation patterns and assess gene expression in chromosomal regions that are genetically and biologically linked to the COVID-19 host response, comparing these patterns in immune system cells from people with DS to those in age-matched control individuals, we will engineer CRISPR/Cas9-mediated deletions in the strongest differentially methylated sequences and measure effects on gene expression, we will develop an accurate and experimentally tractable mouse model of COVID-19 in DS, and quantitate age-dependence of methylation of the host response genes both in humans and in this well controlled model system. We expect our findings to lead to improved clinical and public health management of COVID-19 both in DS and in the general population.