How does the research grant program work?

Magnetic Resonance Fingerprinting (MRF) to Assess ARPKD Kidney and Liver Disease

Autosomal recessive polycystic kidney disease (ARPKD) is a disorder that affects both kidneys and the liver and can present life-long challenges to affected patients. Several new therapies have shown promise in ARPKD animal models. However, these therapies have not been studied in ARPKD patients because there are no clinically-available, reliable, non-invasive ways to measure the effects of treatment. We have identified two magnetic resonance imaging (MRI) measures that may provide this key missing piece. Unfortunately, MRI studies are long and require patients to sit still, which is not possible for young children. In the proposed studies, we will investigate a novel MRI method, called MR fingerprinting (MRF). MRF may allow these studies to be performed very rapidly, having the potential to allow ARPKD patients of all ages to be part of clinical trials for new therapies.

Screening for Modifiers of PKD Severity Using ENU Mutagenesis

There is good evidence that the severity of polycystic kidney disease (PKD) can be influenced by variations in genes that do not cause the disease itself. These could potentially be novel targets for therapy. We propose to identify such genes by creating mutations that affect disease progression in a mouse model of PKD1.

Deregulated Cholangiocyte Autophagy: A New Target for Polycystic Liver Disease

Polycystic liver disease (PLD) is a group of genetic disorders characterized by development of fluid-filled hepatic cysts arising from biliary epithelial cells. PLD might occur in conjunction with autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD). The treatment options for this disorder are still limited. The overall objectives of this proposal are to: (i) explore the role of deregulated autophagy in the progression of PLD; and (ii) test new strategies for the treatment of PLD using in vitro and in vivo models by targeting cAMP-mediated autophagy in cystic cholangiocytes.

Examining the Role of XBP1 in the Pathogenesis of Protein Folding-associated Polycystic Kidney Disorders

Polycystic kidney and liver diseases belong to a family of genetic fibrocystic disorders that primarily affect the kidney and liver. Previously, we have shown that XBP1, a critical component of the unfolded protein response, and SEC63, one of the autosomal dominant polycystic liver disease (ADPLD) genes, interact genetically to control the severity of the polycystic phenotype in a polycystin-1-dependent (encoded by PKD1, one of the two autosomal dominant polycystic kidney disease genes) manner.

This proposal will allow us to achieve a molecular and genetic understanding of XBP1 in the pathogenesis of polycystic diseases with the potential for designing targeted interventions that can improve clinical practice for affected patients.

The Role of Autophagy in Renal Cystogenesis

We propose an experimental plan to study whether autophagy may contribute to renal cystogenesis. Autophagy is a phenomenon by which cells can eliminate unnecessary or dysfunctional cellular components. Our plan will also include the testing of drugs capable to modulate this process to verify if modulation of autophagy can have an effect in the prevention or progression of renal cystic disease. We propose testing our hypothesis in oral-facial-digital (OFD) type I syndrome, a rare inherited form of renal cystic disease for which we have generated reagents, models and preliminary data.

Modeling Human PKD Cystogenesis With Pluripotent Stem Cells

Human pluripotent stem cells have dual value as personalized laboratory models for human kidney disease and as a potential source of on-demand, immunocompatible kidney replacement tissue. Using these cells, it is now possible to generate human mini-kidney ‘organoids’, which are capable of recreating polycystic kidney disease (PKD) in lab dishes. The goal of the proposed research is to expand the existing findings to understand how human PKD mutations cause cystic disease, to test drugs that intervene with this process and to generate patient-matched stem cell products for application in future clinical trials.

Renal Vascular Function in ARPKD

The objective of this proposal is to initiate investigations into the renal vascular, microvascular and inflammation-related mechanisms contributing to the genesis and progression of autosomal recessive polycystic kidney disease (ARPKD). Previous research in polycystic kidney disease (PKD) has focused primarily on the processes behind cyst formation while the role of the blood vessels inside the kidney in the initiation and progression of PKD has not been investigated. The current proposal joins the expertise of two renal physiologists and a PKD physician/scientist to investigate the linkages between renal vascular function and ARPKD development and progression. The results of these studies will open new areas of investigation and potential therapeutic approaches associated with PKD.

Development of a Computer-aided Decision Support System for PKD

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenic disorders, and is a leading cause of end-stage renal disease. Total kidney volume (TKV) has become the main image-based biomarker for following ADPKD progression. This project will develop automated tools to increase measurement throughput, and explore new image-based biomarkers that will significantly add to the assessment of patient prognosis. It will also have the ability to more quickly judge the effectiveness of interventions.

Polycystin-1 Mediated Cyst Regression

Loss of function of the polycystin-1 protein leads to polycystic kidney disease (PKD). Re-expression of wild-type polycystin-1 in cystic mice causes visible regression of cystic disease, but the mechanism of regression is not known. This proposal will study the functional consequences of re-expression of polycystin-1 in a mouse model of PKD, thereby facilitating future therapies designed to recapitulate the function of polycystin-1 to halt or reverse cystic disease.

Genetic Modifiers of Severe Polycystic Liver Disease (Grant co-funded by the PKD Foundation of Canada)

Severe polycystic liver disease (sPLD) is a rare and poorly understood complication of autosomal dominant polycystic kidney disease (ADPKD) or autosomal dominant polycystic liver disease (ADPLD). It affects mostly women and is associated with symptoms of a “mass effect” (e.g., feeling of fullness after eating a small meal, shortness of breath, abdominal pain and swelling, malnutrition and leg swelling). The treatment for sPLD is currently quite limited, and many patients ultimately require a liver transplant. Our work has the potential to improve clinical prediction and treatment of sPLD by identifying the genetic factors that underpin this complication using a new technology called “Next Generation Sequencing” in a large cohort of sPLD cases from multiple international centers.

Role of Fibrocystin/Polyductin in Health and ARPKD

This proposal tackles a long-standing problem in the field of autosomal recessive polycystic kidney disease (ARPKD), which is caused by mutations of the PKHD1 gene. It will identify and characterize the important cellular defects caused by mutations of the PKHD1 gene. Insights gained will advance our fundamental understanding of the function of the PKHD1 gene and enable us to develop effective therapies for ARPKD.

A Novel Screen to Identify Kinases That Are Activated in PKD Kidneys

Many protein kinases have been shown to be increased in polycystic kidney disease (PKD) kidneys. Inhibiting some of these kinases inhibits cyst growth in animal models of PKD. We have now utilized a non-biased screen to identify new kinases that are increased in PKD kidneys. This proposal will apply this methodology to broadly screen PKD kidneys to identify new kinases that are increased in PKD kidneys, and then assess their relevance to cyst growth in animal models of autosomal dominant polycystic kidney disease (ADPKD). Ultimately, this study should identify new kinases that are potential targets to slow cyst growth in patients with ADPKD.

Vascular Integrity in Zebrafish PKD Models

By studying vascular integrity in zebrafish polycystic kidney disease (PKD) models, this project will provide insight into extra-renal symptoms of PKD, particularly vascular symptoms.

Injury Response Mediated Pathogenesis in Ciliopathies

Multiple human syndromes exhibit cysts in the kidney that cause significant morbidity and mortality adding substantially to U.S. health care costs. The cellular basis for most cystic kidney disorders is dysfunctional cilia; however, the role that the cilium plays in the kidney is not well understood. In this proposal we test the hypothesis that cilia are needed for regulating signaling between macrophages and the epithelium following injury, and that when cilia are disrupted the deregulation of these signals establishes an environment that causes increased cell proliferation, cyst expansion and renal fibrosis.

The roles of DNA methylation in autosomal dominant polycystic kidney disease

In this study, we will identify aberrant DNA methylation signatures associated with ADPKD and investigate the functional roles and the underling mechanisms of DNA methyltransferase, DNMT1, in regulating cyst progression, and will test whether de-methylation of hypermethylated DNA mediated by DNMT1 delays cyst growth in vivo. In particular, we will use whole-genome bisulfite sequencing (WGBS) to examine the DNA methylation profiles of normal human and ADPKD kidney samples. We will also identify novel DNMT1 target genes in regulating renal epithelial cell proliferation, apoptosis and ciliopathy during cyst development. Our study will identify the methylation of specific genes in PKD associated signaling pathways and in pathways not previously studied in PKD, which should forward our understanding about the roles of DNA methylation in ADPKD progression. Accomplishing this project will lead to a better understanding of the mechanism of renal cyst formation and will provide novel therapeutic targets for ADPKD treatment.