The ultimate goal is to determine the mechanisms and factors that establish and maintain tubular diameter, to understand the pathobiology of PKD, and to use this information to find a therapy for PKD.
The function of the kidney critically depends on the proper structure of its tubule system, yet regulation of tubular diameter is a poorly understood phenomenon. Cystic diseases of the kidney offer unique opportunities to study these processes. My research focuses on the molecular basis of renal cystic disease and renal tubular morphogenesis.
Autosomal dominant polycystic kidney disease (ADPKD) affects approximately 1/1000 Americans. Cysts arise at all stages of life, and gradually expand to replace normal renal parenchyma. This process results in end stage kidney failure (ESKF) in approximately half by the 6th decade, accounting for approximately 5 percent of all cases of ESKF. Autosomal recessive polycystic kidney disease (ARPKD) is rare (1/20,000) but more severe. Therapies for both at present are limited to managing the complications. We have, however, made great progress in understanding their pathobiology and the role of the normal PKD gene products in regulating tubular morphology.
Mutations in either of two genes, PKD1 and PKD2, cause all forms of ADPKD. Mutations appear to compromise gene function, and much data implicate a molecular recessive model as responsible for initiating cyst growth. PKD1 and PKD2 encode components of a receptor-channel complex that likely has ciliary and non-ciliary functions. Using orthologous mouse models, we have demonstrated unsuspected, complex development-stage specific consequences of Pkd1 inactivation that are linked to metabolic pathways. These models also have been used to show that PKD genes are essential for proper form and function of multiple other organs. As a complementary approach, we have developed cell culture systems that model cyst and tubule formation. We are pursuing several parallel lines of inquiry regarding the relationship between PKD proteins, cellular metabolism, matrix, and planar cell polarity pathways.
ARPKD is a second interest. We identified the gene mutated in this disorder, PKHD1, and have shown that it likely encodes a very large membrane-associated protein that undergoes Notch-like proteolytic processing. We have developed a series of mouse lines and cell culture systems to model the disease and study the protein, and we have shown genetic interaction between the PKD1 and PKHD1 loci. Current efforts are focused on determining its function in kidney and liver development.
While the PKD gene products polycystin 1 (PC1) and polycystin 2 (PC2) are known to be essential for establishing and maintaining normal tubule structure, we do not know how they do this. Several lines of evidence suggest that they function as a receptor-channel complex, but what they sense and signal is poorly understood. Though numerous pathways have been reported to be dysregulated in cystic epithelia, it is unclear how these link back to the function of the PC1/PC2 complex, which pathways are dysregulated at the earliest stages of cyst formation, and which are altered as secondary consequence of cystic dilations. We also do not understand why cysts form immediately after gene inactivation in young mice but take months to arise in older animals. What factors preserve tubular structure during this interval, and what triggers the subsequent failure? Understanding these processes is important not only from a pathobiological standpoint, but also to design more specific therapies. We also need better tools for assessing the progression of disease so we can better evaluate the effectiveness of clinical interventions. Clinical trials are testing promising drugs, and some have reported encouraging results. However, the measure of improvement is often kidney/cyst size, which doesn't always correlate with improvement in kidney function. A more thorough understanding of PKD biology will likely shed light on this matter, but in the meantime biomarkers of early progression and additional measures of outcome in clinical trials should be sought and evaluated.