Established by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in 1999, the Interdisciplinary Centers for PKD Research (ICPKD) are a partnership of scientific investigators from various disciplines who use complementary and integrated approaches in PKD research.
The studies proposed by the ICPKD foster and extend the development of new approaches into the causes, early diagnoses, and improved treatments for both the autosomal dominant form of PKD (ADPKD) and the recessive form (ARPKD). Institutions selected for this program are domestic and have extensive scientific expertise in the areas of cellular and molecular biology, genetics, protein chemistry, structural biology, immunology, pathology, physiology, nutrition, epidemiology, clinical trials, and animal model and drug development.
Center grants such as the ICPKD have proven to be a valuable way to promote multidisciplinary interactions and to provide the shared resources needed to address complex biomedical problems, such as therapy of PKD. Centers also can provide the basis for generating technologies that can be applied by other investigators and clinicians in many medical centers throughout the nation.
Polycystic Kidney Disease
As the fourth leading cause of end-stage renal disease (ESRD) in the United States, PKD contributes appreciably to the associated health care costs for renal failure. A striking feature of PKD is the variability with which it affects patients. Some develop only a modest number of renal cysts during their lifetime and may not be aware of being affected by this disorder. Others develop a massive number of renal cysts and may reach renal failure at an early age.
It is not unusual for cysts to also develop in the liver and within the systemic vasculature. Recent evidence indicates that besides the documented cyst enlargement and interstitial fibrosis, apoptotic loss of non-cystic nephrons is a significant component of the pathology of PKD and may contribute to the progressive loss of renal function.
Despite the salient changes in the structure of the kidney and the fact that ADPKD is one of the most common, potentially lethal genetic diseases known, little systematic research on the cellular mechanisms of the disease was carried out until the past two decades. Since then the growth of knowledge regarding this disease has been almost exponential.
The identification and cloning of the PKD1 gene in 1995, the subsequent discovery of its protein product, polycystin 1, and the sequencing of polycystin 2 in 1996 have led to further significant progress in studying this disease. The latter success can be attributed largely to the development of a PKD mouse model, which has allowed the study of the disease, especially in identifying the gene for ARPKD. Numerous mouse cystic kidney mutations have been described and further exploitation of these mutants and their genetic modifiers should continue to provide powerful resources to study genes and genetic interactions involved in PKD.
Goals and Scope of ICPKD Research
Although most recently the major focus of research on PKD has been to identify the genetic factors that cause the development of cysts and the progression of cyst-related changes within the kidney, the emphases of this initiative are more extensive. The following research goals are potential areas of investigation that may be considered in developing innovative studies:
- Define primary and secondary mutagenic mechanisms of PKD1 & PKD2
- Localize and clone genes for other forms
- Identify genetic loci or genes that modify the PKD disease process
- Clone the ARPKD gene
- Develop genomic reagents useful to these goals
Biology of Polycystin Function:
- Define the structural topography of PKD1-2 proteins and their interacting partners
- Define cellular and biochemical functions of PKD1-PKD2 and their downstream mediators
- Identify genes responsible for renal cystic development and the progression of renal dysfunction in animal models
- Develop physiological measurements in murine models of PKD
Pathogenesis and Progression:
- Define the basis for increased epithelial proliferation
- Define the role of inflammation in disease progression
- Define the role of the renal microvasculature in disease progression
- Develop novel markers or end points to monitor the progression of renal dysfunction in PKD
- Develop means to monitor renal dysfunction before the decline in GFR
- Elucidate control of fluid secretion and accumulation i
Innovative Therapeutic Strategies:
- Explore treatments based on new pathogenic insights
- Explore innovative therapies to ameliorate the course of disease using pharmacologic and gene therapeutic approaches in animal models
- Explore innovative therapies to ameliorate the course of disease using pharmacologic therapeutic approaches in patients
- Identify and initiate innovative treatments in specific cohorts of patients with unusual clinical characteristics (including extra-renal manifestations of disease) or rates of progression of renal disease
Core facilities are shared resources that enhance the productivity of, or in other ways benefit, a group of investigators working to accomplish the stated goals of the ICPKD. Cores are designed to furnish a group of investigators with some technique, service, determination, or instrumentation in a manner that enhances the research in progress, consolidates manpower effort, and contributes to cost-effectiveness by providing a service at lower cost and possibly higher quality than if each investigator were to attempt the same activity individually. Cores usually provide one of the following:
- Technology that lends itself to automation or preparation in large batches (e.g., radioimmunoassay and tissue culture)
- Complex instrumentation (e.g., electron microscopy or mass spectrometry)
- Animal preparation and care
- Technical assistance and training (e.g., molecular biology)
Teaching investigators and/or their staff members' new techniques and methodologies is also an important function of the cores. Other types of activities also may be supported by an ICPKD, including optional pilot and feasibility (P&F) and enrichment program.
NIDDK/KUH Project Officer: Catherine Meyers, M.D., 301-574-7717.