Nephrology Research- A Look in to the Past and Anticipation of the Future
For the Division of Nephrology, research has always been at the forefront of the minds of its physicians, scientists, coordinators and staff. Here is a brief look at what the division has accomplished in the past year as well as a look into the future.
Dr. Frank Park provides the following about his research activities: “In the past year, our lab has focused on the role of Activator of G protein Signaling 3 (AGS3) as a critical regulator of epithelial hyperplasia. We have published our work on AGS3 and PKD in the premier kidney journal, Journal of American Society of Nephrology,. The AGS3 in IRI study was performed in collaboration with Dr. Kevin Regner and his lab, and is currently under review at FASEB J. NIH grants were submitted for both of these studies, and fortunately both were considered to be innovative and scored (23rd percentile for AGS3 in PKD and 38th percentile for AGS3 in IRI). In the upcoming year, we will continue with our present work and dissect the signaling pathways involved in mediating AGS3 activation in the renal epithelial cell. We will re-submit our grants back to the NIH and hopefully, be funded by the middle of next year to continue working on this exciting new project.”
While Dr. Park and his team work on AGS3, Dr. Andrey Sorokin had this to say about his current research; “During the last year we have identified a number of signaling proteins, including adaptor protein Engulfment and cell motility 1 (ELMO1), as candidates for the posttranslational regulation of Cox-2 activity. In studies planned for the next year we will uncover the mechanism of protein-protein interaction between Cox-2 and protein-regulators and establish the physiological significance of novel posttranslational regulation of Cox-2 in the progression of glomerular diseases. The significance of proposed studies is that this new knowledge will open novel strategies to combat progression of glomerular renal diseases.”
“Even though hypertension induced nephropathy is among major causes of ESRD, which emerges as a looming health care crisis in the US, the pathophysiological mechanisms mediating the progression of hypertension induced nephropathy accompanied by renal vascular dysfunction remain unknown. We have been studying the mechanism by which Endothelin-1 (ET-1) signaling contribute to renal vascular dysfunction in hypertension-induced nephropathy. We have recently demonstrated ET-1-dependent signaling through the adaptor protein p66 Shc, guanine nucleotide exchange factor 1Pix and transcription factor FOXO3a in renal cells. It is important because this previously unknown signaling cascade links ET-1-induced age-related renal pathologies with signaling through a p66 Shc pathway known to affect longevity and resistance to oxidative stress. Based on our findings obtained in vitro we now attempting to elucidate the role of distinct signaling pathways in the progression of hypertension-induced nephropathy in vivo using Zinc-Finger nucleases-mediated gene targeting in a well characterized rat model of salt-sensitive hypertension and glomerular disease. In collaboration with investigators from Department of Physiology at MCW we have already made p66 Shc knockout rats with targeted disruption of p66 Shc gene in SS genetic backgrounds. Knockout rat strains are being bred to homozygosity prior to comparison of renal function in SS rats and p66 Shc rat knockouts. p66 Shc knockout rats generated via embryo microinjection of zinc-finger nucleases offer unique opportunity to study the role of p66 Shc-mediated signaling in hypertension induced renal vascular dysfunction.”
For the year 2010 there are six studies to be considered. Two research trials with clinical application have been completed and closed: FAVORIT, a vitamin study, looked at Folic Acid for Vascular Outcome Reduction in Transplantation. Specifically, this was an NIH supported trial on the effect of a high dose combination of folic acid, vitamin B12, and vitamin B6 on arteriosclerotic cardiovascular disease outcomes in chronic, stable renal transplant patients. FACT, ancillary to the vitamin study, was a cognitive study which looked at cognition and the effect of lowering homocysteine in renal transplant subjects. Specific aims of the ancillary study were to evaluate cognitive function as it relates to plasma homocysteine in renal transplant recipients and to determine the cognitive effect of homocysteine-lowering treatment in this population. One device study, Palindrome is also expected to complete and likely close in 2010. This study compares the performance and longevity of a split-tip versus a symmetric tip hemodialysis catheter.
The clinical side of research for the division of Nephrology has also had a busy year and is looking ahead to an active 2011.
For the year 2010, one conversion drug trial, LCP-Tacro 3001, has currently ended enrollment and is expected to complete and close. This is a phase III prospective study comparing the effectiveness and safety of conversion from twice daily capsules to once daily capsules for prevention of acute allograft rejection in stable kidney transplant patients. The research will be used to approve a new once a day dosage of the investigational drug. LCP-Tacro 3002 a De Novo drug trial is anticipated to begin in 2011.
Four drug studies currently closed to enrollment, but active in study procedures, include the BENEFIT study (008), BENEFIT-EXTENDED CRITERIA DONOR study (027), BENEFIT CONVERSION study (010), and the Jak-3 trial. Each of these has gone into long-term extension. The first two BENEFIT series studies are De Novo; the third is a conversion trial. The hypothesis of this study series looks at superior preservation of renal function with similar rates of subject and graft survival, and with no clinically important increase in acute rejection. A secondary hypothesis is superior measured glomerular filtration rates (GFR) and lower incidence of chronic allograft nephropathy (CAN) as compared with current immunosuppressive medication. In the Jak-3 extended trial a new drug is compared to standard medications for use after kidney transplantation for prevention of acute rejection.
One study, Epidemiology of Cancer, continues with open enrollment. This is a single center survey analysis from the Medical College of Wisconsin looking at cancer in renal transplant recipients. With transplant recipients living longer, and with and increasing prevalence of cancers seen in this population, it is critical to continue this exploration as post transplant cancer impedes improving success after renal transplantation.
Additionally, it is anticipated that three other studies, although technically still open, will end their clinical applications before the end of this year. BKV Source, an independent project, is based on the hypothesis that the source of BK virus in renal transplant recipients is the donor, as opposed to the recipient. The BK virus infection can manifest as nephritis which can lead to irreversible renal graft loss. Granzyme, is an independent pilot study correlating cellular granzyme and perforin levels with rejection, versus BK viral nephritis rejection in renal transplant recipients. And finally, Scripps (NIH) Genomics, had an overall objective to apply the latest technologies in genomics to establish gene expression profiles, (recipient and donor), in order to advance our understanding of clinical kidney transplantation. All three clinical trials have the potential to close in late 2010 or early 2011.
The future continues to look bright for the division of Nephrology they work toward achieving their research goals through publication, in the lab, and through clinical trials.
Article written by Frank Park, PhD, Andrey Sorokin, PhD, Pat Lyman, and Antonio Grasso