The overarching aims of this Center are to help advance the clinical, research, and educational goals of the ChiLDREN grant with a particular emphasis on engaging cutting-edge genome studies as a basis for discovery, innovation, and improvements in outcomes and care. As such, the aims of this application are not only to provide comprehensive research opportunities for all children who fit enrollment criteria for ChiLDREN throughout the Southeastern US. We are also planning to embark upon 3 genomically-centered Research Aims:
Aim 1 : Explore the genetic determinants of outcomes in biliary atresia (BA). We hypothesize that by detailed, broad-based, unbiased exploration of individual patient genomic determinants (e.g., whole exome sequencing), we will be able to assign genetic categorization of children into those able to adapt well post-Hepatoportoenterostomy (HPE), and those who do not. Intial findings have identified variants in a pathophysiologically-relevant gene that associate with poor outcome after HPE.
Aim 2 : Determine causes of BA with Laterality Defects. This will proceed by identifying carefully-phenotyped individuals with biliary atresia with laterality defects. To date, 20 trios have been exome sequenced, and analyses are ongoing, with expectations to validate such findings in the larger, BA cohort in ChiLDREN.
Aim 3 : Explore GGT as a marker for development and progression of portal hypertension in BA subjects with native livers over the age of 2. Preliminary data support the concept that an elevated GGT at age 2 predicts the development of portal hypertension indices and we will utilize the ChiLDREN database to validate and fine- tune these findings, with the goal being to develop GGT as a biomarker of disease progression in BA. The latter will have relevance for a planned study of a novel FXR agonist in these older BA patients in this consortium. The final proposal is to make a single-site exome sequencing and bioinformatics locale within the Emory Genetics Lab under the guidance of Dr. Madhuri Hegde, with close interweaving of longitudinal information from the DCC to develop models, stratify patients, and predict outcomes. Taken together, the focus upon exome sequencing in this population of diseases that manifest early in life and can be stratified into readily-identifible outcome groups, are arguably the ideal group of patients ever collected to deliver etiologic and therapeutic discoveries in cholestasis. For these serious pediatric liver diseases, none with effective medical therapies, studies like these will not only benefit this population, but are likey to provide a deep understanding of the mechanisms underlying liver disease progression in patients of all ages.
With ongoing involvement of this Center, we hope to be able to contribute to the achievement of all the goals of ChiLDREN, arguably the most robust and feasible means to make a difference for children with cholestatic liver diseases ever developed. This CC's participation expects to provide continued high enrollment, embark upon novel studies on genetic determinants of the causes and progression of pediatric liver diseases, and finally, help develop investigations of a new anti-cholestatic and anti-fibrotic therapeutic, to hep fill the current therapeutic void.
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