- Prof. Andrey Sorokin, Principal Investigator
- Dr Sundaram Hariharan, Co-Investigator
- Medical College of Wisconsin, Milwaukee, USA
- Prevention of Virus-associated Nephropathy after Renal Transplantation
In recent years, nephritis induced by BK virus (BKV), a non-enveloped double stranded DNA polyomavirus, has become a severe problem after renal transplantation and there is a critical need to better define the molecular mechanisms of BKV entry into its target cells. An objective of the proposed study is to identify the protein component of the BKV receptor and to develop pharmaceutical agents capable of mitigating BKV entry into human proximal tubular epithelial cells (HRPTECs). HRPTECs are considered to be one of the main natural targets of BKV. The identity of the receptor the BKV uses to enter HRPTEC is unknown and no specific pharmacological agent preventing BKV nephritis is available. Currently, the only efficient therapy against BKV nephritis appears to be a reduction/change of immunosuppressive agents, but this may increase the inherent risk of rejection. In our preliminary studies, we have established that caveolar endocytosis is critical for BKV infection of HRPTEC and revealed several important steps of the BKV intracellular trafficking pathway in HRPTEC. Furthermore, our data suggest that the antagonist of binding of peptide Endothelin-1 to G-protein coupled receptor prevents BKV infection of HRPTEC. Using small interfering RNA (siRNA)-mediated gene silencing we expect to establish the identity of protein that serves as a receptor for uptake of BKV into the human kidney. We will also screen a panel of endothelin receptor antagonists for their ability to prevent infection of HRPTEC. These studies will provide proof of concept data for the development of this class of drugs as potential targets for the prevention and possibly treatment of BKV nephritis. Ultimately, these studies may reduce the incidence of BKV nephritis and improve long-term graft survival after renal transplantation.