Systems biology of acute and chronic multi-organ failure in children with congenital heart disease

PROJECT SUMMARY Approximately 25% of children with congenital heart disease (CHD) require intervention in the first year of life. Although surgical mortality has decreased, the incidence of acute and chronic postoperative morbidities remains high. Morbidities are primary drivers of hospitalization, long-term outcomes, and cost, and are most common in

children requiring neonatal surgery and those undergoing staged palliation for single ventricle heart disease (SVHD). While our patients struggle with these morbidities daily, our understanding of the mechanisms and molecular phenotypes of organ injury/recovery remain limited. Our preliminary data suggest that targeting a

limited number of biomarkers/pathways is insufficient to address the complicated reality of CHD. Instead, diagnostic approaches allowing simultaneous measurement of hundreds of molecules (“omics”) paired with high dimension data analysis techniques could represent a better strategy. Our team has been highly productive in

detailing the acute metabolomic and proteomic response to CHD surgery. We also found that the robust datasets generated through this work provide an excellent environment for training junior researchers in data science methods. Under this K24 proposal, we will use our two established cohorts (neonatal surgery and longitudinal

SVHD palliation) to expand beyond the acute postoperative period, exploring the systems biology of subacute and chronic morbidity in our CHD patients. We will also leverage these high dimension datasets to train the next generation of researchers interested in using data science techniques to improve the lives of children with CHD.

Overall Hypothesis: Postoperative injury and abnormal development following CHD surgery result in disruption of the circulating proteome and metabolome during initial injury, repair, and longitudinal growth. Serial measurements of the proteomic and metabolomic signature will validate novel candidate biomarkers of key

chronic morbidities and identify previously unexplored interactions among diverse molecular pathways in a systems biology approach to understanding this complex pathophysiology. Specific Aim 1 (New Science under the K24): Utilize proximity extension assay technology to perform longitudinal measurement of the circulating proteome in the convalescent period after neonatal CHD surgery

and determine the proteomic phenotype/changes in targeted protein biomarkers preceding two critical postoperative morbidities: subacute intestinal injury and chronic neurodevelopmental delay. Specific Aim 2 (Career Development): Expand my skills in the analysis of omics and deep clinical data through

a combination of experiential and didactic training, with an emphasis on learning novel strategies to integrate and analyze multiple streams of high dimensional data. Specific Aim 3 (Mentoring): Using our established cohorts as a training platform, develop a pipeline of new patient-oriented physician-scientists interested in learning and applying data science methods towards

mechanistic, diagnostic, and therapeutic discovery in children with CHD.