Sullivan, Kelly D PHD

This project will test the transformative hypothesis that dysregulated DNA rereplication in response to cellular stress contributes to the development of Trisomy 21 (T21) and subsequent pathophysiology of Down syndrome (DS). This project arises from the observation the interferon receptor cluster encoded on chromosome 21 undergoes DNA rereplication and targeted transient site-specific gene amplification in response to viral infection in healthy cells; however, this process is impaired in T21 cells. To test our hypothesis, we will employ a combination of human and mouse culture models and a mouse in vitro fertilization model to define the extent of DNA rereplication dysregulation in T21 and how DNA rereplication could contribute to the development of T21 and comorbidities associated with DS.

Individuals with Down syndrome are predisposed to a wide range of co-occurring conditions, including many gastrointestinal conditions. This proposal will test the hypothesis that innate alterations in inflammation, metabolism, and the microbiome result in enteric nervous system dysfunction that drives these conditions. Insights from these studies could not only increase our understanding of gastrointestinal disease in Down syndrome, but also identify new therapeutic strategies for their management.

Many of the neurological conditions that co-occur in people with Down syndrome (DS) arise from brain cell alterations that are subtle and progressive in nature, making their categorical detection a challenge for researchers and clinicians. We postulate that the DS brain is predisposed to traumatic brain injury (TBI)-induced acute and long-term disabilities based on our findings that a mouse model of DS is hypersensitive to a single mild TBI and exhibits long-term impairment. This transformative research project aims to use mild TBI as a sensitizing probe to visualize the subtle and hard-to-detect DS-associated cellular and molecular alterations with the overarching goal of discovering new therapeutic strategies for people with DS.

Down syndrome (DS), the genetic condition caused by triplication of chromosome 21 (T21), is the most common chromosomal abnormality and a leading cause of intellectual and developmental disability. Although it is accepted that T21 causes genome-wide dysregulation of gene expression programs, little is known about how T21 affects gene expression across different tissues and organs, and how these effects contribute to the developmental and clinical hallmarks of DS. To address this knowledge gap, this proposal aims to generate a comprehensive atlas of tissue-specific gene expression changes caused by T21, matched to detailed metrics of organ development and architecture.

There is an urgent need for therapeutic interventions to treat the symptoms of SARS-CoV-2/COVID-19 associated with severe outcomes; including cytokine release syndrome which is implicated in acute respiratory distress syndrome, heart failure, and death. The work outlined in this proposal will test the ability of FDA- approved JAK inhibitors to rescue cytokine production and multi-tissue inflammation in a mouse model of non- infectious immune hypersensitivity. This work will provide pre-clinical data in support of ongoing clinical trials aimed at treating harmful immune responses in COVID-19.