This NIDDK K01 application is designed to provide Dr. Katharina Hopp with the scientific, technical, and career training to enable her transition into an independent investigator studying mechanisms controlling Autosomal Dominant Polycystic Kidney Disease (ADPKD) cystogenesis. The project builds on Dr. Hopp's expertise in the genetics and cell biology of ADPKD, and extends her training in the immunological and microenvironmental aspects of this disease. The proposal encompasses a five-year training plan under the primary mentorship of Dr. Raphael Nemenoff, an expert in the cancer microenvironment, and an Advisory Committee comprised of accomplished immunologists and PKD physician/scientists. The project will investigate the functional role of T- cells in cyst initiation and progression, underlying mechanisms, and novel therapeutic approaches. Features of ADPKD parallel those of cancer, including induction of proliferation, genomic instability, and increased inflammation. In cancer, targeting T-cells in the tumor microenvironment has shown clinical success; however, the functional role of T-cells in PKD is poorly understood. Preliminary data generated by Dr. Hopp showed that, in a well-established murine ADPKD mouse model developed by Dr. Hopp, distinct T-cell subpopulations increased correlative to disease severity and localized specifically to cystic lesions. Importantly, depletion of CD8+ T-cell, which are generally anti-tumorgenic, increased disease progression, highlighting the functional importance of these cells in halting cyst progression. However, regulatory T-cells, which are generally pro- tumorgenic, rose early in disease, suggesting that distinct T-cell subpopulations may have opposing effects on cystogenesis. In addition, both PD-L1 and PD-1, components of an immune checkpoint pathway, were significantly increased in the mouse model and PKD patient kidney sections. Targeting this pathway has been therapeutically effective in numerous cancers. Thus the central hypothesis of this project is that interactions of distinct T-cell populations with the cystic microenvironment/epithelium result in both anti- and pro- cystogenic effects, and targeting T-cells represents a novel therapeutic strategy for APDKD.
The specific aims of this project are (1) Define the functional role of T-cell subpopulations in cyst initiation and progression; (2) Elucidate the mechanisms how T-cells alter cellular pathways in the cystic epithelium; and (3) Evaluate the efficacy of checkpoint inhibitors in ADPKD. The project will be supported by the University of Colorado, Denver's outstanding PKD Program, the Renal Division, and the Immunology Department. The PKD Program has been successful in translating preclinical data into clinical trials and is motivated to incorporate results of this project into future clinical trial designs. In addition to the above aims, Dr. Hopp will (1) develop a strong knowledge of immunology and related novel technique/model systems; (2) expand her professional proficiencies in manuscript/grant writing, mentoring, and reviewing duties; and (3) submit a competitive R01 application towards the end of this K01 expanding upon findings from this application.
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common monogenic disorders and the leading cause of end-stage renal disease; nonetheless, no FDA approved therapy is available to patients and past research efforts focused on the cystic epithelium for drug treatment development have shown only modest success. This proposal interrogates the functional role of T-cells in cyst initiation and progression, as novel avenue for therapeutic approaches. Targeting T-cells has shown great efficacy in alleviating multiple cancer types, a pathology similar to ADPKD on the cellular and molecular level; however, the functional role of T-cells in cystogenesis and their potential as therapeutic target is currently understudied.