Awardees

Khusali Gupta  |  Lawrence Research Group  |   American Heart Association Predoctoral Fellowship Award

Project Summary/Abstract: Down syndrome (DS) is a common chromosomal disorder, occurring in 1 in 700 live births in the US. Half of newborns with DS begin life with congenital heart defects (CHD) requiring surgical correction, and there is evidence of potentially related vascular deficits. Children with DS are typically happy and sociable but have mild-moderate intellectual disability which can progress to severity in adults. High risks for other co-morbidities include pulmonary hypertension, autism, and almost inevitable early-onset Alzheimer Disease; any deficit in angiogenesis could contribute to these conditions. The Lawrence lab has pioneered a strategy to “silence trisomy”, by translating the basic mechanism of X-inactivation, the XIST gene, to chromosome 21 (chr21). Upon induction, XIST RNA spreads across and silences all ~250 genes across that Chr21, in cis, and this was shown to correct known hematopoietic pathogenesis from DS-induce pluripotent stem cells (iPSCs), in vitro. Using this tightly controlled system the lab recently showed that chr21 over-expression has a direct cell autonomous effect on endothelial cells which impairs micro-vessel formation in vitro and impacts gene networks important in both heart development and angiogenesis. The lab has now developed a modified method to silence just a small part of chr21, the proposed “Down Syndrome Critical Region” (DSCR). This now provides the opportunity to directly test the important hypothesis that a small cluster of genes, within the DSCR, cause major DS phenotypes. Using the available inducible iPSC system, I will test if silencing the DSCR enhances formation of micro-vessels by human endothelial cells in vitro. In addition, I am working to translate “trisomy silencing” with XIST in vivo to a mouse model (carrying human chr21) which exhibits CHD. This work utilizes an innovative approach with high significance for investigating the causes of CHD and vasculature in DS, but will also test a potentially transformative concept, relevant for other chromosomal disorders, which collectively are more common than DS and frequently impact heart structure or function. The work proposed will forward the prospects of “chromosome therapy” as we advance the basic biology of cardiac and vascular deficits in DS.