Multiple genes involved in Hepatorenal fibrocystic disorders HRFDs have been identified and in most cases the affected genes encode cilia proteins. These data led to the hypothesis that cilia dysfunction is a major contributing factor to cyst formation and that HRFDs are members of a group of disorders termed the ciliopathies. In addition to PKD, HRFD ciliopathies include Meckel Syndrome (MKS), Nephronophthisis (NPHP), Joubert Syndrome (JBTS), and Bardet-Biedl Syndrome (BBS). Animal models with HRFDs have contributed greatly to our understanding of the pathogenesis of HRFDs and fundamental knowledge about cilia and ciliopathies. These models have been used extensively to evaluate pathogenicity of human disease alleles, for testing genetic interactions between disease loci, to analyze disease progression, and to assess candidate cilia regulated signaling pathways. Importantly, well characterized model systems are the initial testing platform for therapeutic strategies. To accelerate the pace of research into the causes and potential treatments of HRFDs, the Engineered Models Resource (Core B) will facilitate better utilization of a wide range of highly informative models through the following three aims:

Specific Aims:

Aim 1: Generation of New Animal and Cell Models of HRFDs. The core will continue to generate innovative conditional, congenital, and human mutant allele models with mutations in HRFD genes (PKD, BBS, MKS, NPHP, and JBTS) in mice and C. elegans and expand services to include CRISPR engineered mutations in zebrafish and mouse, and in renal epithelial cell lines. This will facilitate analyses of pathogenic mechanisms involved in HRFDs, the assessment of human disease alleles, and future testing of therapeutic strategies by the user base and the Center’s Therapeutic Screening.
Aim 2: To Establish In Vivo Biosensors to Study Signaling Pathways Involved in HRFD Ciliopathies. To facilitate in vivo analyses of HRFD related pathways, the Core will establish a series of biosensor lines for pathways involved in cyst development and progression. The initial biosensors will assess changes in cytosolic and ciliary Ca2+ and cAMP levels in mice and zebrafish. Additional lines will be engineered in other key pathways implicated in cystic kidney disease (e.g. MCP1, mTor, Stat3 and Stat6) and lines requested by center members. The Core is also establishing a CiliamCherry biosensor for intravital visualization of cilia that will complement the existing CiliaGFP line or the existing GCaMP Ca2+ biosensor. These biosensor lines are needed to rapidly assess changes in pathway activity in live animals and to evaluate the efficacy of potential therapeutic trials in HRFDs.

Aim 3: To Generate and Distribute HRFD Related Biologicals to the Center’s Investigator Base. One of the primary missions of the Core is to provide investigators with access to biological materials and live model systems that carry mutations in HRFD related genes or that express fluorophore tagged HRFD related genes. The Core will readily distribute mutant and transgenic mice (including the popular IFT88Flox and CiliaGFP strains), zebrafish, and C. elegans lines to our members. Importantly, access to these models is essential to accelerate genetic, biochemical, and cellular analyses of pathways underlying HRFDs, as well as facilitate testing therapeutic strategies. In addition, we will provide biological samples, including cells, tissues, urine samples, DNA, RNA, and protein that are derived from these in vivo models, to members for exploratory studies, to test hypotheses, and for feasibility analysis prior to establishing the live model at the investigator’s home institution.

Contact Dr. Bradley Yoder ( to discuss potential projects utilizing the Engineered Models Core.