The research laboratory of Peter C. Harris, Ph.D., focuses on genetic diseases of the kidney, especially polycystic kidney diseases (PKD). PKD constitute a range of inherited disorders that often result in renal failure and even death. Dr. Harris' laboratory employs a range of genetic and cell biological approaches to understand the etiology and pathogenesis of these disorders.
Dr. Harris' research group previously identified the major gene for the common autosomal dominant PKD (ADPKD) and the gene for autosomal recessive PKD (ARPKD), and more recently identified two genes for the syndromic PKD, Meckel syndrome (MKS).
In these disorders, Dr. Harris' studies are focused on screening for disease-causing mutations and other variants that can modify the phenotype. By employing genotype/phenotype studies, he is determining the extent to which the variability in disease presentation and progression is explained by simple genetic factors.
The research of Dr. Harris is funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). He is associate director of the Mayo Translational PKD Center, which coordinates PKD research activities at Mayo Clinic. He also hosts the PKD Foundation-funded ADPKD Mutation Database, which describes more than 2,000 variants to the ADPKD genes.
To better understand the function of the proteins encoded by PKD genes, Dr. Harris has generated mouse models that eliminate expression, overexpress the protein or mimic specific mutations. These studies have defined phenotypes associated with protein loss/gain and allowed the pathogenesis of the disorder to be analyzed in detail.
By carefully modulating the expression employing a hypomorphic allele in ADPKD, it has been possible to carefully mimic the gradual disease development seen in the human disease and develop a model suitable for testing novel therapeutics.
Accumulating evidence indicates that PKD is a disease associated with defects of primary cilia. Dr. Harris' group is analyzing the processing — including cleavage and glycosylation — of the large, membrane-bound ADPKD-related protein polycystin-1 to determine how these changes influence its location and function.
Similar studies are aimed at understanding the role of the ARPKD protein, fibrocystin, and the MKS protein, meckelin. Analysis of mutant products is also helping with the understanding of disease pathogenesis. Important recent discoveries indicate that a major site of ADPKD and ARPKD expression is in urinary vesicles, exosomes, which may mediate an urocrine signaling system.
Significance to patient care
Dr. Harris' studies are improving diagnostics and prognostics of these disorders.
- Homer W. Smith Award (for contributions to knowledge about the functioning of the kidney), American Society of Nephrology, 2008
- Inaugural Lillian Jean Kaplan International Prize for Advancement in the Understanding of Polycystic Kidney Disease, PKD Foundation and the International Society of Nephrology, 2003