DESCRIPTION (provided by applicant): The Kansas PKD Research and Translation Core Center (Director: James Calvet) is comprised of an Administrative Core, Pilot & Feasibility Program, Educational Enrichment Program, and four Biomedical Research Cores: Gene Targeting, Epigenetics, Biomarkers, and Clinical Research. At its foundation, the Center has an active and growing research base of outstanding PKD investigators on which it proposes to build innovative cores and a robust P&F program providing opportunities for new investigators to enter the PKD field and to conduct cutting-edge research. The mission of the PKD Center is "The promotion of research leading to a better understanding of polycystic kidney disease and the discovery of targets for therapy and development of clinical trials ultimately for improved patient outcomes." The central theme of this proposal is "Target identification for PKD therapy development." The Kansas PKD Research and Translation Core Center will achieve the broad goals and objectives articulated by the center's mission and central theme by accomplishing these four specific aims: 1) To support PKD researchers locally and nationally by developing innovative biomedical research cores. 2) To develop a skilled, collaborative, multidisciplinary basic science and clinical research investigator base. 3) To develop partnerships within the institution, with shared support facilities, and with cooperating institutions. 4) To enhance the research environment to support ongoing projects and to develop new research directions.

Project Narrative: Relevance to the Research on Public Health Polycystic kidney disease (PKD) is a very common, inherited disease characterized by the abnormal growth of countless fluid-filled cysts in the kidneys of PKD patients. The progressive enlargement of these cysts in affected kidneys leads to renal failure in about half of patients; and patients often have hypertension, cerebral and aortic aneurysms, and heart valve defects, and often die of cardiovascular complications. The National Institutes of Health (NIH) considers PKD to be a high priority disease because of its high prevalence in the population; because of its high morbidity and mortality; and because of the very high costs associated with dialysis, transplantation, and long-term follow-up care. The University of Kansas Medical Center has a tradition of interdisciplinary research in polycystic kidney disease, which began with the recognition that PKD represents an abnormality in the growth and proliferation of kidney tubule cells. While the mechanisms underlying these processes are not completely understood and are still the subject of intense investigation, they have provided a strong rationale for developing PKD therapeutics that can specifically inhibit targets associated with cyst growth and enlargement. As such, the mission of the PKD Center at Kansas is “The promotion of research leading to a better understanding of polycystic kidney disease and the discovery of targets for therapy and development of clinical trials ultimately for improved patient outcomes.” Basic research conducted at the University of Kansas identified the intracellular second messenger cyclic AMP as the key abnormality driving both cyst growth and cyst-filling fluid secretion, and that research led to the development of tolvaptan for therapy. The success of the tolvaptan clinical trial attests to the effectiveness of our approach, which starts with target identification followed by studies to better understand the broader physiology. While we are now beginning to understand the fundamental cyst growth mechanism sufficiently well to focus drug development on cyclic AMP stimulated pathways, we are also exploring and investigating other fundamental mechanisms underlying the pathogenesis and progression of PKD with the goal of discovering new targets for drug development and PKD therapy. We believe that PKD is a very unique disease and thus will offer many challenges for therapy, as drugs will have to be efficacious as well as safe over decades, and ultimately it would be best to treat PKD in its earliest stages, and thus we have emphasized early and childhood PKD in our proposal. The Kansas PKD Research and Translation Core Center is offering four highly innovative biomedical research cores and pilot and feasibility research opportunities related to the theme “Target identification for PKD therapy development.” These cores are the following: the Gene Targeting Core will offer expert CRISPR/TALEN gene editing in Pkd1 hypomorphic background strains to discover and validate PKD pathway interacting proteins and signaling components both in vivo and in cell culture for the identification of new targets for drug development; the Epigenetics Core will offer a range of reagents, tools, resources, and expertise to genetically test the role of epigenetic regulators in controlling known PKD signaling pathways or for the discovery of new pathways that can be targeted for drug development; the Biomarkers Core will develop a repository of blood and urine samples from a cohort of early-stage PKD patients for the discovery and evaluation of serum, urine, and urinary exosome biomarkers specific to early PKD, with the involvement of Myriad-RBM to develop and validate, rapid biomarker testing for PKD therapy development; and the Clinical Research Core will develop clinical trials services and platforms that will help investigator-initiated efforts bring drugs into patient trials by offering consultative services, a PKD patient registry, clinical resources and personnel to help in conducting trials, and a user-friendly, multi-site, data-rich PKD database for observational studies. The Kansas PKD Core Center is also offering five pilot and feasibility grants per year and an educational enrichment program to maximize the development of research related to the Core Center theme and to accelerate the growth of the biomedical research cores and the training of new PKD physician- scientists.