Validation of ZHX2 as a Novel pVHL E3 Ligase Substrate and Its Role in Kidney Cancer
Abstract
Scientific Objective and Rationale: The estimated new cases and deaths from kidney (renal cell and renal pelvis) cancer in the Unites States in 2014 were 63,920 and 13,860 respectively. Kidney cancer incidence has been increasing steadily for the past several decades although the reasons for this are unclear. Loss of Von Hippel-Lindau (pVHL) is one of major reasons that cause kidney cancer. Loss of pVHL leads to a set of protein stabilization downstream, which contributes to kidney cancer. Therefore, it is critical to identify those proteins that are affected by pVHL loss and lead to kidney cancer, which will help us design therapeutic invention strategies to target these drivers for kidney cancer. In our current proposal, we identified such a protein, ZHX2, which may act as a pVHL substrate and contribute to kidney carcinogenesis. We aim to (1) validate the function of ZHX2 in mediating pVHL loss induced renal carcinogenesis; (2) elucidate the mechanism by which ZHX2 contributes to renal cell carcinogenesis; and (3) examine whether ZHX2 protein levels can be used to predict patient survival and clinical outcomes in kidney cancer. Career Goals: A Peer Reviewed Cancer Research Program Career Development Award will have a great impact on my career. First of all, receiving this prestigious award will give me significant external recognition, which will distinguish me as a "promising young scientist with great potential." It will also facilitate my chances to establish collaborations with senior research faculty and clinicians, increase my chances of recruiting highly qualified postdoctoral fellows, both of which are critical for my career development. Second, it will present me with a lifetime opportunity to explore the questions that I am highly interested in at the beginning of my career, which could contribute significantly to potential kidney cancer therapeutics. This award will provide me with sufficient funding and time to pursue the novel ideas I proposed, and allow me to shape my future research directions. It will also allow me to obtain enough preliminary data that will make this project competitive for R01 funding later and will thus serve as a hot-start to set up my exciting research program. More importantly, I believe that the important goal of my research career is to translate what we learn from basic science into the clinical relevance by exploring novel therapeutic modalities in kidney cancer therapy. I believe that I have all necessary elements to successfully run my own independent research program and make major contributions towards eventually curing kidney cancer. Impact: Our ability to develop targeted therapies against kidney cancer is heavily dependent on a more detailed understanding of the molecular mechanism of pVHL-related renal carcinogenesis through generation and examination of accurate in vitro and in vivo model systems. Our proposal aims to study the etiology and potential treatment strategies for kidney cancer patients with pVHL loss of function, which accounts for approximately 70% of clear cell renal cell carcinoma (ccRCC). Identification and characterization of unique pVHL substrates may help elucidate novel signaling pathways that are regulated by pVHL in kidney cancer. Functional characterization of ZHX2 in kidney cancer may help us identify new drug targets for kidney cancer and shed light on novel therapeutic modalities to treat this disease. Military Relevance: The proposed work can potentially significant impact on military beneficiaries because (1) cigarette smoking, which accounts for 30% of active duty personnel, is a significant risk factor for renal cell carcinoma; (2) occupational exposure to heavy metals, paints, organic solvents and other combat related chemicals significantly increases the risk of renal cell carcinoma; (3) Agent Orange, one of the herbicides and defoliants used by the U.S. military, was linked to kidney cancer in U.S. Veterans; (4)
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510599
Entities
People
- Qing Zhang
Organizations
- United States Army
- University of North Carolina at Chapel Hill