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K Awardees Workshop Project Summaries Karam Aboudehen, Ph.D. UNIVERSITY OF MINNESOTA, MINNEAPOLIS, MN Deregulation of Long Noncoding RNA in the Pathogenesis of Autosomal Dominant Polycystic Kidney Disease Polycystic kidney disease (PKD) is characterized by the formation of cysts, which originate from the epithelial tubules of the nephron. Progressive growth of the cysts causes damage and loss of functional nephrons, ultimately leading to end-stage renal failure. The pathophysiology of PKD is incompletely understood, and only one FDA-approved treatment (tolvaptan) exists today. Long noncoding RNAs (lncRNA) – defined by a length >200 nucleotides and absence of a long open reading frame – are a class of non-protein-coding RNAs implicated in a range of diseases. The nature and extent of involvement of lncRNAs in PKD was not previously investigated. Utilizing two independent PKD mouse models, the applicant identified Hoxb3os, a highly conserved lncRNA, which was downregulated in mouse and human ADPKD. Deletion of Hoxb3os in kidney cells resulted in increased phosphorylation of mTOR and its downstream targets. Consistent with activation of mTOR signaling, Hoxb3os mutant cells displayed increased oxidative phosphorylation, increased cell proliferation, and decreased autophagy. The Hoxb3os mutant phenotype was partially rescued upon re- expressing wild-type Hoxb3os in knockout cells. Importantly, deletion of Hoxb3os in wild-type mice recapitulated the in vitro molecular phenotype and resulted in increased mTOR phosphorylation and subsequent increased cell proliferation, and defective autophagy. The overarching hypothesis for this K01 project is that downregulation of Hoxb3os exacerbates cyst formation and/or disease progression by dysregulating multiple pathways, including mTOR signaling. To test this hypothesis, the applicant will decipher the mechanism by which Hoxb3os inhibits mTOR signaling, identify novel Hoxb3os-regulated pathways, and determine the contribution of Hoxb3os to cyst formation in a mouse model of ADPKD. The applicant has assembled an interdisciplinary team of senior investigators to guide the proposed research and provide mentorship during his transition to independence. He will have full access to the University's shared resources (mouse genetics laboratory, high-throughput sequencing, mass spectrometry and proteomics, bioinformatics). The applicant's training plan includes mentorship in core technique and concepts, generating and analyzing data, publishing and presenting results, completing coursework (in mouse genetics, biostatistics, RNA biology, computational methods, bioinformatics), and developing other requisite skills (in leadership, grant proposal development) needed to thrive as an independent investigator. Results from the proposed studies will form the basis for an R01 application to be submitted in the fourth year of this career development award. The applicant's long-term goal is to dedicate his career to advancing basic and translational research on cystic kidney disease as an independent investigator at an academic institution. As a kidney researcher with a deep interest and proven track record in molecular biology, he is uniquely positioned to answer the questions set forth in this proposal and to rapidly advance the mechanistic understanding of lncRNAs in PKD pathogenesis. Maisam Abu-El-Haija, M.D. CINCINNATI CHILDRENS HOSP MED CTR, CINCINNATI, OH Predicting Severity and Improving the Outcomes of Pediatric Pancreatitis Project Summary/Abstract The incidence of pediatric Acute Pancreatitis (AP) has been rising to 1/10,000 cases, close to adult incidence. AP in pediatrics remains understudied with outcomes poorly defined. Previous studies in pediatric AP are mostly single-centered and retrospective in nature, and thereby insufficient for understanding the natural history. A high percentage (15-30%) of patients develop severe acute pancreatitis (SAP) with increased morbidity, increased length of hospital stay and cost. To date, there is no pediatric AP study that examines progression prospectively like we plan through our design, there is no validated pediatric prognostic severity system to improve outcomes of AP. Diabetes can result from AP in a subset of patients, and that leads to increased morbidity especially if underdiagnosed, given that there is no current method for screening post AP. The primary goal of my proposed career development is to acquire additional comprehensive training in biostatistics, study design, epidemiology and outcome research through risk modeling, to acquire the skills necessary to build multicenter collaborations to study AP risk stratification and management that lead to the improved outcomes and decreased morbidity and mortality. I am an Assistant Professor of Pediatrics and a board certified Gastroenterologist in the Division of Gastroenterology, Hepatology and Nutrition in the Department of Pediatrics at Cincinnati Children’s Hospital Medical Center (CCHMC). CCHMC is committed to improving the health outcomes of children through innovative research. The exceptional environment at CCHMC facilitates the development of young investigators by having essential elements through core resources, expert mentorship, as well as the potential for internal collaboration. The pancreas Care Center at CCHMC is one of only a few pediatric pancreas centers in the United States and has an established referral pattern, with 70-90 new patients referred per year. My mentors Dr. Lee A. Denson- a nationally recognized leader in pediatric gastroenterology, Dr. Sohail Husain- a national expert and scientist in pediatric pancreatology, Dr. Woo- an expert in epidemiology and outcome research are invested in my training and guiding my path to be an independent investigators. The primary objective of this project is to improve outcomes of AP by decreasing SAP and improve screening for prediabetes. This will be accomplished through our prospective longitudinal study design. Specific Aim 1 to validate and optimize our previously generated SAP model by adding more factors, applying the new SAP definition, incorporating therapy effect, and incorporating MMPs and TIMPs as novel biomarkers. Specific Aim 2 to build a model to predict prediabetes post AP and understand the role of expanded gene testing in disease progression to prediabetes. Our proposal will help us better understand SAP and progression to prediabetes to fill the knowledge gap. Successful completion of this study has the potential to lead to improved outcomes by building clinical tools that facilitate management, and potentially lead to targeted therapies for AP in pediatrics. A. Lenore Ackerman, Ph.D., M.D. CEDARS-SINAI MEDICAL CENTER, LOS ANGELES, CA The Urinary Microbiota and Host Inflammation in Lower Urinary Tract Symptoms PROJECT SUMMARY Storage lower urinary tract symptoms (LUTS), which include urinary urgency, frequency, nocturia, painful urination, and bladder pressure/discomfort, refer to patient experiences when the bladder is unable hold urine appropriately. These highly prevalent symptoms are chronic and debilitating, substantially degrading physical activity and quality of life. Yet despite the heavy burden of storage LUTS on public health, little is understood of the pathophysiology of these symptoms, limiting diagnosis, treatment, and prevention options. Humans harbor diverse microbial communities that live in symbiosis with healthy hosts but are frequently altered in disease. The role of these alterations is unclear, but mounting research suggests that microbial components may interact with human tissue to alter organ function, tissue permeability, and even central nervous system responsivity. We and others have used novel, state-of-the-art DNA sequencing methods to identify bacteria and fungi residing within the urinary tract and describe global differences in urinary microbial communities in patients with storage LUTS. We have yet to understand how these differences impact bladder pathophysiology, but our preliminary data suggest that shifts in these microbial communities underlie or reflect storage LUTS symptoms and correlate with increased local and systemic inflammation. We postulate that interactions of these changed communities with the host alter local and systemic inflammation and increase immunologic activation of bladder urothelial cells, generating inflammatory signatures characteristic of specific urinary symptoms. Based on similarities to other inflammatory diseases, we hypothesize that this inflammation becomes pathogenic in susceptible hosts with dysregulated microbial recognition, possibly mediated by genetic differences in host responsiveness to microbial components. Using state- of-the-art microbial profiling techniques, we will identify changes in urinary bacterial and fungal communities linked to storage LUTS in patients. We will also identify disease-associated variations in inflammatory markers and urothelial activation and associate these findings with specific microbial signatures and symptom patterns. We will perform a targeted characterization of genetic polymorphisms associated with dysregulated inflammatory responses to microbes to explore the contribution of host susceptibility in these conditions. Few previous studies have examined the urinary microbiota; this proposal is the first to integrate multi-omic datasets with clinical metadata to allow the discovery of clinically useful disease markers, microbial and inflammatory, and place them into the context of disease mechanisms and host risk factors. This study may promote
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