O-GlcNAcylation as a Therapeutic Target in Autosomal Dominant Polycystic Kidney Disease
Abstract
This application addresses FY21 PRMRP Topic Area, Polycystic Kidney Disease, and the Area of Encouragement, research on the underlying pathobiology and molecular mechanisms of polycystic kidney disease, including studies of genetic factors, cyst formation and growth, the role of cilia, and factors that modify disease progression and/or severity. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is among the most common, life-threatening monogenic diseases affecting approximately 1:1000 individuals worldwide, including among military personnel, Veterans, and their families. ADPKD causes progressive growth of large fluid-filled renal cysts, which causes kidney injury and can lead to end-stage renal disease. The disease also causes pain, hypertension, bladder infection, vascular complications, and liver cysts. Diagnosis of ADPKD typically occurs in the early 30s, so most young adults who enter the military are unaware that they have the disease. The medical burden of ADPKD affects quality of life and will impact a Soldier’s ability to perform to his/her maximum potential. There is one FDA-approved therapy, but which has variable effectiveness. Additionally, substantial side effects related to dehydration render the therapy contraindicated for Soldiers in combat. Thus, there is a critical need to develop more therapies and a cure. The molecular etiology of renal cystogenesis is complex, but studies indicate the disease mechanism originates from a defect in the primary cilium. The primary cilium is a sensory organelle that detects and converts mechanical and chemical signals into signaling pathways. Recently, altered cellular metabolism has also emerged as an important contributor to ADPKD pathogenesis, and studies suggest primary cilia and cellular metabolism connect. We propose that a nutrient sensor pathway acts both as a novel potential therapeutic target and molecular link between the ciliary and metabolic defects in ADPKD. Using mouse models, patient-derived in vitro cell models, and a recently developed in vitro 3D renal tubule mimetic, we anticipate our experiments will show that ADPKD renal cystogenesis is mitigated by inhibition of this nutrient sensor, and that novel regulatory mechanisms, feedback loops, and in turn, additional therapeutic targets will be revealed. Finally, our 3D renal tubule mimetic will be among the first in vitro 3D models of ADPKD amenable to regulated changes in fluid flow and has potential to be used for future screening of pharmacological compounds. Thus, completion of this proposal will present a much needed novel therapeutic target and novel avenues to identify additional therapeutic strategies against ADPKD. This will contribute toward alleviating the immense medical burdens of this common genetic disease, afflicting Service Members, Veterans, their families, and civilians alike.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210035
Entities
People
- Pamela V Tran
Organizations
- United States Army
- University of Kansas Medical Center