The Center for Translational Pediatric Research (CTPR) seeks to investigate how pediatric diseases develop from a systems biology and mechanistic approach, with the ultimate goal of identifying the intersections of disease and development, which will produce targets for therapeutic intervention and the development of new treatments. Systems biology is an integrated approach examining all events within cells, tissues, and organisms that lead to a particular outcome. By applying a systems biology approach to the study of pediatric diseases, the CTPR hopes to expand existing knowledge of pediatric disease development and contribute to new therapeutic targets. The long term goal of the CTPR is to build an innovative, multi-disciplinary pediatric research center that utilizes cutting-edge systems biology technologies and state-of-the-art translational research to study pediatric diseases.
The CTPR is seeking applications to the Pilot Project Program.
The Pilot Project Program awards $75,000/year in direct costs to a junior scientist whose research interests closely match the focus of the CTPR. Two awards are issued every year. Applications should follow NIH R21 format and guidelines. Interested individuals should email Dr. Alan Tackett (AJTackett@uams.edu) to ensure the proposed research fits with the mission of the CTPR.
Joe Opferman, PhD, Associate Member, St. Jude Children’s Research Hospital
Shawn Polson, PhD, Associate Professor of Computer & Info Sciences and Biological Sciences, Delaware Biotechnology Institute
Sean Taverna, PhD, Associate Professor of Pharmacology and Molecular Sciences, Johns Hopkins University
Linda Thompson, PhD, Adjunct Professor, Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center
Mike Washburn, PhD, Professor of Pathology and Laboratory Medicine, The University of Kansas Medical Center
The Internal Advisory Committee (IAC) consists of five well-experienced institution leaders and serves as the bridging mechanism between the CTPR and the institution.
Larry Cornett, PhD, Vice Chancellor for Research and PI of the Arkansas INBRE grantMartin Hauer-Jensen, PhD, Professor of Pharmaceutical Sciences, Pathology, and Surgery and PI of the Center for Host Response to Cancer Therapy
Charlotte Hobbs, PhD, Professor of Pediatrics and Executive Associate Dean for Research for the College of Medicine
Richard Jacobs, PhD, Chair and Professor of Pediatrics, former President of ACRI
Laura James, PhD, Professor of Pediatrics, PI of the UAMS Clinical and Translational Sciences Award
The Proteomics Core provides a crucial piece of the systems biology puzzle - the large-scale identification and quantification of proteins and protein posttranslational modifications.
Rick Edmondson, PhD, Associate Professor of Medicine and Sam Mackintosh, PhD, Research Assistant Professor, Department of Biochemistry and Molecular Biology
Renny Lan, PhD, Instructor, Department of Biochemistry and Molecular Biology
Lisa Orr, BS
Aaron Storey, PhD
The overall theme of the CTPR is to study how pediatric diseases develop from systems biology and mechanistic standpoints with the ultimate goal of identifying points in the intersection of disease and development which, in turn, will produce targets for intervention and the development of new treatments. The Proteomics Core provides a crucial piece of the systems biology puzzle - the large-scale identification and quantification of proteins and protein posttranslational modifications.
Jason Farrar, MD., Assistant Professor of Pediatrics, UAMS
Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by severe anemia due to failure to produce red blood cells, congenital abnormalities, and predisposition to cancer. DBA has been established as a disorder of ribosome production; however, little is understood about the downstream effects of an altered ribosomal milieu or the way in which these alterations lead to erythroid failure in DBA. The research team hypothesize that specific changes in translational output of the ribosome-limited erythron underlie the selective failure of the erythropoiesis in DBA. The long term goal of this work is to develop a mechanistic understanding of the anemia in DBA in order to identify novel targets for therapeutic interventions.
Xiawei Ou, PhD, Associate Professor of Radiology and Pediatrics, UAMS
Maternal obesity is a serious health concern for pregnant women and their offspring. Recent studies have revealed negative associations between maternal obesity during pregnancy and long-term cognitive functioning and neurodevelopment of children. However, the exact mechanisms behind these associations is unknown. Preliminary analyses and functional connectivity evaluations revealed a trend of structural/functional differences in the newborn brain associated with maternal obesity. These findings indicate that brain imaging of newborns can provide for sensitive, early detection of effects of maternal obesity on offspring brain development. The goal of this project is to identify biomarkers of the neuroprogramming effects of maternal obesity on offspring’s brain that are predictive of neurodevelopmental outcomes at later ages and to provide maternal interventions that promote proper cognitive function and neurodevelopment.
Laxmi Yeruva, PhD, Assistant Professor of Pediatrics, UAMS
Breastfeeding is associated with a variety of positive health outcomes in children and is recommended for the first 6 months of life; however, 50-70% of infants in the US are formula-fed. The goal of this study is to understand the regulators that drive breastmilk-associated advantages in terms of gut development and immune function. It has been suggested that breastfed infants have advance immune system development compared to formula-fed infants, but the underlying mechanisms remain to be fully elucidated. This study aims to use a piglet model of feeding to determine the effects of early diet on gastrointestinal development and function and to what extent these effects are mediated by a diet driven gut microbiota. The ultimate goal is to improve infant formula by adding components that lead to similar outcomes as seen in breastfed infants, or to alter microbiota, via probiotics and prebiotics, to help boost the immune system.
Boris Zybailov, PhD, Assistant Professor of Biochemistry and Molecular Biology, UAMS
Chronic kidney disease (CKD), a progressive decline in kidney function, is a growing health problem. CKD in children can be especially devastating, with 30 times higher mortality rates than in the general pediatric population. In 40% of cases, leads to an irreversible loss of kidney function, end-stage renal disease, for which no cure exists aside from dialysis and kidney transplant. CKD raises urea levels in the body, which alters the gut microbiome leading to a decreased consumption of waste and erosion of cellular barriers. Toxins can then travel more easily throughout the body, leading to inflammation and further kidney damage. Resistant starch is a type of pre-biotic that is not fully broken down and absorbed, but rather turned into short-chain fatty acids by intestinal bacteria. In related studies, RS diets were associated with decreased plasma toxins and inflammations, indicating RS diets may be considered an alternative treatment for CKD.
Marie Burdine, PhD, Assistant Professor of Surgery, UAMS
Pediatric organ transplantation is the only option for thousands of children suffering from end-stage organ disease. Organ transplantation is life-saving, however; the immunosuppressive medications pediatric patients are required to take to preserve donated organs and prevent rejection are expensive and can have dangerous side effects including cancer and heart disease. My work is focused on developing novel immunosuppression therapies for transplant patients that reduce side effects and ease financial burden. Our laboratory has recently shown that DNA-PK, a protein involved in DNA damage repair, plays a critical role in initiating both the humoral and cell-mediated immune response pathways. These pathways are responsible for acute and chronic organ rejection. DNA-PK inhibitors block activation of the immune cells involved in organ rejection, B and T cells. Currently, transplant patients are required to take multiple drugs to inhibit both immune cells, therefore; the use of a single reagent would be unique and beneficial. The goal of our work is to perform the first preclinical studies using mouse skin allograft models to test the effectiveness of DNA-PK inhibitors as post-transplant immunosuppression therapy.
Samantha Kendrick, PhD, Assistant Professor of Biochemistry and Molecular Biology, UAMS
The present challenge in achieving successful, long-term treatment in pediatric lymphoma is the knowledge of whether targeted-therapies currently in clinical trials for adult patients are efficacious due to the poorly defined molecular mechanisms that underlie lymphoma in the pediatric setting. Lymphomas are the third most commonly diagnosed childhood malignancy with diffuse large B-cell lymphoma (DLBCL) as a major subtype of pediatric non-Hodgkin’s lymphoma (NHL). DLBCL is also the predominant, aggressive NHL in adults and recent gene expression profiling studies suggest the molecular biology and clinical pathology of pediatric DLBCL differs from adult DLBCL. Two main entities, the germinal center B-cell-like (GCB) and the activated B-cell like cell-of-origin (COO) characterize adult DLBCL; however, there is a considerable enrichment for the GCB COO in pediatric-associated DLBCL. In further contrast, pediatric DLBCL differ in the expression of well-known prognostic factors including MYC, indicating alternative mechanisms may be involved in pediatric DLBCL pathogenesis. MYC levels are elevated in pediatric DLBCL and as a sought after target in cancer, may offer as a potential candidate for targeted therapy in children with DLBCL. Despite advances in the treatment of pediatric mature B-cell lymphomas, curative outcomes for refractory and relapsed disease are dismissal and along with frequent acute and chronic toxicities, there is an urgent need for novel approaches to therapy. Knowledge of the pathways involved in pediatric DLBCL pathology is critical to developing and applying optimal lymphoma therapies in pediatric patients. Preliminary data from our laboratory and collaborators supports oncogenes MYC and PAK2 important for tumor cell growth and survival as promising targets in DLBCL. We recently demonstrated a novel transcription inhibitor of MYC substantially reduces MYC expression and chemosensitizes DLBCL cell lines. We hypothesize that DLBCL in pediatric patients arise from alternative pathways than those observed in adult patients and these additional molecular signals will offer insight into developing targeted therapies.
Josh Kennedy, M.D., Assistant Professor in Pediatrics and Internal Medicine, UAMS
Human airways precision cut lung slices (PCLS) prepared from organ donors consist of many relevant cell types of the respiratory tract situated in their native micro-anatomical environment. This system maintains ciliary motility and responsiveness to contractile agonists, including carbachol (CCh). Our research within this platform illustrates increased responsiveness to CCh in PCLS derived from donors with a history of asthma [PCLS(A)] 48h after infection with rhinovirus (RV). These responses are comparable to what is seen clinically during exacerbations of asthma. In clinical practice, however, not every asthmatic responds to RV infection in a similar manner. Studies in experimental RV infection suggest the importance of allergy (Th2) in patients that are responsive to methacholine. In these studies, subjects with high total IgE (>371 IU/mL) had clinically worse symptoms to RV and had AHR to methacholine as compared to either low IgE subjects or non-allergic controls. Therefore, we propose to compare AHR in PCLS(A) from donors with a Th2-high signature (e.g., enhanced expression of POSTN, CLCA1, SERPINB2, DPP4, and CST1)12 to those with low in airway epithelial cells. We hypothesize that different pathways may be involved in Th2-high donors compared to Th2-low donors or donors without asthma with regard to the AHR afforded to the airways during RV infection. To test this hypothesis, we will use a systems biology approach, utilizing transcriptomics, proteomics and integrated bioinformatics within the Centers for Translational Pediatric Research (CTPR) to evaluate differences between groups. These types of discovery-phase studies are appropriate for pilot funding because they provide hypothesis-generating data that will set the stage for an R01 submission within 1-2 years.