UAB HRFDCC LogoThe Center has four Biomedical Research Cores that integrate existing intellectual and technological resources at the University of Alabama at Birmingham, George Washington, and the Medical University of South Carolina to provide services and resources that enable innovative studies within the Center’s thematic areas. The Cores are 1) Core A: The Hepatorenal Fibrocystic Disease Translational Resource; 2) Core B: The Engineered Models Resource; 3) Core C: The Cellular Physiology Resource; and 4) Core D: The Therapeutic Screening and Drug Discovery Resource. A brief summary of each Core is provided below and in more detail in the individual Core sections. Importantly, all of the Directors of the Cores have robust research/clinical programs in HRFDs.

Core A Leadership Core A Goals and Objectives Core A Resources and Services Core B Leadership Core B Goals and Objectives Core B Resources Study Enrollment Information Core C Leadership Core C Goals and Objectives Core C Resources and Services Core D Leadership Core D Goals Core D Resources Center Leadership Pilot and Feasibility Program Pilot Voucher Program Postdoc Research Fellowship Program Summer Research Intern Program Educational Enrichment Drug Discovery and Clinical Trials

Core A: The Hepato-Renal Fibrocystic Diseases Translational Resource

Director: Lisa M Guay-Woodford, MD; Co-Director: William E. Grizzle MD, PhD.

The major objectives of the Translational Resource are to expand the catalogue of genetic mutations in ARPKD and other HFRD patients, to facilitate access and sharing of clinical and genetic data as well as bio-specimens (DNA and tissues) for the Investigator Base, and to expand the portfolio of educational material related to HRFD. These objectives will provide the impetus for more rapid research progress and community understanding of these disorders. These objectives are being accomplished through the following specific aims: 1) to establish a national resource for clinical data, DNA, and tissue biopsies from human patients with HRFDs; 2) to develop algorithms to identify causative genetic mutations in HRFD patients and utilize a suite of new tools to assess the pathogenicity of sequence variants; and 3) to expand the portfolio of educational information and tools to encompass the HRFD spectrum of disorders.

Core B: The Engineered Models Resource

Director: Bradley Yoder, PhD; Co-Directors: Robert A Kesterson, PhD and John M. Parant, PhD

The goal of the Engineered Models Core is to generate and provide investigators with novel model systems for in vivo and in vitro functional analyses of cilia and cystic kidney disease related genes and their affected pathways. The specific aims of the Core are: 1) to generate new engineered models (including human disease alleles) to study cilia function and HRFDs in cell lines, C. elegans, zebrafish, mice, and rats; 2) to generate informative biosensor and reporter lines for intravital and live-cell analysis of HRFD and cilia-associated pathways implicated in cyst development and progression; and 3) to increase the pace of research in HRFD by providing biological reagents (tissue samples, blood, urine, protein, DNA, etc.) from a wide spectrum of HRFD models. These resources will facilitate pilot studies to test new hypotheses and to generate preliminary data for grant submissions without requiring the lines be established at an investigator’s home institution.

Core C: The Cellular Physiology Resource

Director: Phillip Darwin Bell, PhD; Co- Directors: Wayne R Fitzgibbon, PhD; Gary Hardiman, PhD; and Michael Janech PhD

The main objectives of the Cellular Physiology Resource are to provide the Investigator Base with well controlled resources and precise and reproducible physiological readouts that are important for understanding mechanisms involved in cystogenesis. The aims of the Core are: 1) to provide methodologies to assess physiological changes in models of HRFD in vivo; 2) to establish mTERT and hTERT immortalized cell lines from HRFDs patients and mouse models; 3) to provide approaches to assess physiology and molecular changes associated with HFRD mutations. The breath of the techniques and services provided by Core C could not easily be applied to such a wide spectrum of HRFD models as available through the Center, nor are not readily available in most individual laboratories.

Core D: Therapeutic Screening and Drug Development Resource

Director: Michal Mrug, MD; Co- Directors: Gene Siegal MD, PhD; and Kurt Zinn PhD.

The objective of the Therapeutic Screening and Drug Development Resource (Core D) is to provide the Investigator Base with the essential tools, models, and technologies, along with an integrated therapeutics development plan to accelerate preclinical stages of HRFD drug discovery. This is being done using a wide spectrum of HRFD animal models and human or animal cell lines. These objectives will be accomplished through three aims: 1) to develop in vitro predictive assays to identify HRFD lead compounds; 2) to develop in vivo predictive translational models of HRFDs to enhance efficacy of assessment in preclinical testing; and 3) to develop advanced HRFD-specific toxicology and safety screens that will advance the pace to clinical trials. These resources and services will catalyze progress towards a unified long-term goal of developing safe pharmacotherapies for individual HRFDs.