Polycystic Kidney Disease: Mechanistic Dissection and Discovering Precision Therapeutic Targets
Autosomal-dominant polycystic kidney disease (ADPKD) is a life-threatening monogenic disease that affects nearly 1 million people in the U.S. alone. ADPKD represents a very large unmet medical need, currently without remedy. It is characterized by progressive growth of cysts that progressively replace normal tissue, which eventually leads to kidney failure, requiring chronic dialysis or transplantation. PKD is caused by inhibitory mutations in PKD1 or PKD2, two interacting membrane proteins that activate a signaling pathway required to suppress cystogenesis. However, a major barrier in this field has been the lack of a tractable system for dissecting the ADPKD pathway.
The Salic lab in the Department of Cell Biology at Harvard Medical School has developed a rapid and robust quantitative cell-based system to molecularly dissect the PKD pathway. Using this system, the lab has identified direct transcriptional targets of the PKD pathway, including several genes implicated in cystogenesis. This ongoing project employs a genome-wide CRISPR/Cas9 screen to further discover novel components of the PKD pathway, particularly negative regulators, which could serve as targets for rescuing defective signaling in disease. The lab aims to use this knowledge to discover novel small molecules capable of correcting the cellular defects that cause the disease.
Intellectual Property Status: Patent(s) Pending