2015 Cell Signaling, Kidney, Target Identification, Immune System Function
2003/2004 Biomarkers, Kidney
2009 B Cells, Kidney, New Treatments
TNF antagonism in SLE
2015: Faulty Biological Clock in the Kidney May Contribute to Lupus Nephritis
The study and what it means to patients
We are asking if disturbances we have detected to the biological clock that regulates how the kidney functions contribute to the immune system’s attack on this organ. If so, drugs could be developed to reset the clock, stop the immune system’s attack on the kidney, and restore kidney function.
Our bodies have an internal clock that is attuned to the daylight hours and also keeps time to its own intrinsic rhythm. Research shows that our body clock regulates not only our sleep/wake cycle and metabolism, but also the activity of vital organs and our immune system. When the body clock no longer keeps time properly, these systems are disrupted and don’t perform well.
We have discovered that the biological clock is not functioning properly in the kidney of mice with lupus nephritis. Our hypothesis is that dysfunction of the clock amplifies to inflammation and scarring of the kidney tissue that occurs in lupus nephritis. My team will explore which genes keep time in the kidney and how they become out of sync. Ultimately, our goal is to create a mouse model where we can turn these critical genes on and off to restore or disrupt the clock. Our research will yield valuable insight into how the body’s timekeeping abilities could regulate kidney functions—and help us understand the differences in timekeeping in healthy kidneys compared to lupus kidneys. This research has implications for novel treatment approaches in lupus nephritis.
Scientific Abstract: Altered renal circadian rhythm in SLE nephritis
Circadian oscillation in expression of approximately 10% of the transcriptome synchronizes various behavioral, biochemical, and physiological processes, allowing all organisms to anticipate and respond to changes in their environment. Disruption of circadian rhythm has important consequences for human health. Control of circadian rhythm is dependent on a set of transcription factors that regulate each other through feed-forward loops. There is both a central pacemaker and a set of organ specific pacemakers. In the kidneys for example, GFR, renal blood flow, urine excretion and electrolyte excretion are all subject to daily oscillations. Furthermore circadian oscillations in the immune system affect responses to pathogens and inflammation.
We have recently found a disturbance of expression of key clock transcriptional regulators in the kidneys of mice with SLE nephritis. We hypothesize that dysfunction of the renal circadian clock contributes to the amplification of inflammatory circuits in lupus nephritis. Our goals are to confirm circadian dysfunction at protein level, to determine whether the dysfunction affects the renal parenchyma and/or infiltrating inflammatory cells and whether deficiency or overexpression of the master transcriptional regulator BMAL1 impacts on lupus severity. Our findings set the stage for testing therapies that target the molecular clock.
2009: TNF antagonism in SLE
In this innovative study, Dr. Davidson takes on the challenge of teasing apart the complex mechanisms by which a protein (a cytokine) called “TNF-alpha” apparently protects against systemic lupus at the same time that it increases inflammation and worsens lupus kidney disease.
Drugs that block TNF-alpha already have successfully produced remission in a small group of people with lupus nephritis whose condition hadn’t responded to other treatments. But TNF-alpha also increased the production of damaging auto-antibodies, raising the risk of a disease flare. This dual and conflicting result may occur because TNF-alpha binds two different receptors.
By shedding light on how TNF-alpha both protects and worsens lupus damage in several animal models of lupus, Dr. Davidson aims to set the groundwork for designing smart, selective blockers of TNF-alpha that can help without hurting at the same time.
2003/2004 Biomarkers of Kidney Damage
Dr. Davidson set out to determine if certain early markers (“biomarkers”) of kidney damage and remission in a mouse model of immunotherapy-induced lupus remission might be applicable to humans.
Could inflammatory molecules in the urine of mice similarly indicate nephritis onset or remission in humans?
Dr. Davidson ultimately published her findings that remission phases are associated with loss of activated macrophages from the kidney—which suggests that these are the cells that cause the damage.
She also identified six genes expressed by activated macrophages that are down-regulated during remission. These are all potential biomarkers that may be useful for early detection of lupus nephritis and in assessing responses to new therapies in clinical trials.
“I now have two postdocs working on this project and an active collaboration with nephrologists at Mount Sinai Medical School and at the University of Michigan.” – Dr. Davidson in 2010
Mechanism of action of transmembrane activator and calcium modulator ligand interactor-Ig in murine systemic lupus erythematosus. Ramanujam M, Wang X, Huang W, Schiffer L, Grimaldi C, Akkerman A, Diamond B, Madaio MP, Davidson A. J Immunol. 2004 Sep 1;173(5):3524-34.
The current status of targeting BAFF/BLyS for autoimmune diseases. Ramanujam M, Davidson A. Arthritis Res Ther. 2004;6(5):197-202. Epub 2004 Jul 29.
Targeting of the immune system in systemic lupus erythematosus. Ramanujam M, Davidson A. Expert Rev Mol Med. 2008 Jan 21;10:e2.
Block and tackle: CTLA4Ig takes on lupus. Davidson A, Diamond B, Wofsy D, Daikh D. Lupus. 2005;14(3):197-203.
Activated renal macrophages are markers of disease onset and disease remission in lupus nephritis. Schiffer L, Bethunaickan R, Ramanujam M, Huang W, Schiffer M, Tao H, Madaio MM, Bottinger EP and A Davidson. J. Immunol 2008 180: 1938-1947.
Dr. Davidson won a 2-year, $234,000 grant from the Alliance for Lupus Research in 2007 to further characterize the inflammatory macrophages and dendritic cells that she initially described in her LRI-funded work and in 2010 was awarded a $2.4 million RO1 grant from the NIH’S National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
“This project took a long time to get off the ground and I am grateful to the LRI for seeding it. Without this funding we would not have been able to go on to compete successfully for NIH funds. – Dr. Davidson in 2010
Rev. July 2010