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Search Results to Charles Louis Edelstein

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One or more keywords matched the following properties of Edelstein, Charles

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overview My NIH-funded research from 2001-2007 investigated caspases and apoptosis in PKD. We demonstrated that both pharmacologic (caspase inhibitor) and genetic (double knockout caspase-3 cpk/cpk mice) methods of apoptosis inhibition resulted in less apoptosis and proliferation and less PKD. My NIH-funded research from 2008 to 2012 investigated mTORC1 signaling in PKD and we were first to demonstrate that sirolimus attenuates PKD in rat and mouse models. Recently we published the first report of decreased autophagy in polycystic kidneys of cpk mice and Han:SPRD rats. Based on our published and preliminary data and the fact that many of the agents that protect against PKD are autophagy inducers, we developed the hypothesis that PKD is a state of decreased autophagy. We also hypothesized that autophagy inhibition would reverse the protective effect against PKD of known autophagy inducers like caloric restriction, metformin. My grant to study autophagy in PKD is funded by the Dept. of Veteran’s Affairs. My Dept. of Defense funding (2015-2019) was to study novel mTORC1 and 2 pathways in PKD kidneys. We were first to demonstrate that the second generation mTOR inhibitors, the mTOR kinase inhibitors, attenuate PKD in a rat model and that an mTOR antisense that targets both mTORC1 and 2 also attenuates PKD in a Pkd2 knockout mouse model. Cardiac disease is the commonest cause of death in PKD. During our studies of mTOR in PKD kidneys, we noticed enlarged hearts in 5 rodent models of PKD and increased mTORC1/2 signaling in the heart in Pkd1 knockout mice. These data led us to the Aims for the Dept. of Defense Award to determine the effect of genetic or pharmacological inhibition of mTORC1 (4E-BP1) or mTORC2 on cardiac structure and function and mTORC1/2 signaling in the heart in mice with PKD. Our published studies demonstrate the therapeutic effect of sirolimus, ACE inhibitors and statins, VEGFR inhibitors, caspase inhibitors, combined mTORC1 and 2 inhibition, angiotensinogen inhibition, mTOR kinase inhibitors and lack of therapeutic effect of HIF-1 inhibitors in animal models of PKD. These studies demonstrate our expertise in performing therapeutic studies in animal models of PKD. Cysteine proteases and IL-18 in acute kidney injury (AKI) In 1995 we were the first to describe the role of the cysteine protease, calpain, in AKI. In the late 1990s a group of cysteine proteases called caspases, that mediated programmed cell death or apoptosis, were discovered. I received NIH funding to study the role of cysteine proteases in AKI. I focused on caspase-1, also known as Interleukin-1 converting enzyme or ICE, that activates the cytokines IL-1 and IL-18. In two papers in J. Clin. Invest. in 2001 and 2002, we described that IL-18 was both a mediator and biomarker of AKI. I received renewal of my NIH funding to continue the study of IL-18 in experimental AKI. I demonstrated the mechanisms of IL-18-mediated kidney injury and the source of IL-18 in the kidney. Recently, we discovered that IL-33, another IL-1 family cytokine that is activated by caspases, is a mediator of cisplatin-induced AKI. The studies of IL-33 in AKI were funded as a VA Merit Award in 2012 continuing over 10 years of NIH funding of our work on cysteine proteases in AKI. Biomarkers of AKI Our mouse studies in 2001 that IL-18 increases in the kidney and urine in AKI were the first suggestion of the use of biomarkers that come from the kidney to diagnose AKI rather than serum creatinine that has been used since 1917. The IL-18 work was taken to the bedside and we received a patent in 2006 for IL-18 as a biomarker of AKI in humans. We demonstrated that IL-18 is an early biomarker of AKI in patients with delayed graft function and patients post cardiac surgery. I helped establish and was Co-Investigator of an NIH-funded consortium, the Translational Research involving Biomarkers of Early AKI Consortium (TRIBE-AKI),that performed and published multiple clinical studies of biomarkers, including IL-18, as an alternative to creatinine, in diagnosing AKI. The largest AKI biomarker study ever performed of over 1200 patients demonstrated that urine IL-18, urine and plasma NGAL were early biomarkers of AKI and increased before creatinine in patients with AKI. We demonstrated that the biomarkers of AKI in humans go up within 6 hours of the kidney injury and 2 days before serum creatinine. In 2010 (first Edition) and 2017 (Second Edition), I edited a book “Biomarkers in Kidney Diseases”, that included the novel AKI biomarker work. In summary, I have made original discoveries on the role of the cysteine proteases and cysteine protease-derived cytokines in both PKD and AKI. I was the first to suggest that biomarkers like IL-18, that are made by the kidney, may be more promising than creatinine, the conventional way to diagnose AKI. Both our IL-18 biomarker studies in AKI and our mTOR studies in PKD have been translated to the bedside.

One or more keywords matched the following items that are connected to Edelstein, Charles

Item TypeName
Academic Article Calpain inhibition protects against virus-induced apoptotic myocardial injury.
Academic Article Caspases, Bcl-2 proteins and apoptosis in autosomal-dominant polycystic kidney disease.
Academic Article Caspase-1-deficient mice are protected against cisplatin-induced apoptosis and acute tubular necrosis.
Academic Article Caspases and calpain are independent mediators of cisplatin-induced endothelial cell necrosis.
Academic Article Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1beta, IL-18, IL-6, and neutrophil infiltration in the kidney.
Academic Article Caspase-3 gene deletion prolongs survival in polycystic kidney disease.
Academic Article Mammalian target of rapamycin and caspase inhibitors in polycystic kidney disease.
Academic Article Macrophages are not the source of injurious interleukin-18 in ischemic acute kidney injury in mice.
Academic Article Role of caspases in hypoxia-induced necrosis of rat renal proximal tubules.
Academic Article mTORC1/2 and rapamycin in female Han:SPRD rats with polycystic kidney disease.
Academic Article Caspase inhibition prevents the increase in caspase-3, -2, -8 and -9 activity and apoptosis in the cold ischemic mouse kidney.
Academic Article Endotoxemic acute renal failure is attenuated in caspase-1-deficient mice.
Academic Article Pathways of caspase-mediated apoptosis in autosomal-dominant polycystic kidney disease (ADPKD).
Academic Article Caspase inhibition reduces tubular apoptosis and proliferation and slows disease progression in polycystic kidney disease.
Academic Article Caspases as drug targets in ischemic organ injury.
Academic Article Downregulation of the calpain inhibitor protein calpastatin by caspases during renal ischemia-reperfusion.
Academic Article Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure.
Academic Article Proximal tubules from caspase-1-deficient mice are protected against hypoxia-induced membrane injury.
Academic Article Peripheral CD4 T-cell depletion is not sufficient to prevent ischemic acute renal failure.
Academic Article Different ways to die: cell death modes of the unicellular chlorophyte Dunaliella viridis exposed to various environmental stresses are mediated by the caspase-like activity DEVDase.
Academic Article Apoptosis and autophagy in cold preservation ischemia.
Academic Article Renal protection from prolonged cold ischemia and warm reperfusion in hibernating squirrels.
Concept Caspase 8
Concept Caspase 1
Concept Caspase 2
Concept Caspase 9
Concept Caspase 3
Concept Caspase 7
Academic Article NLRP3 inflammasome knockout mice are protected against ischemic but not cisplatin-induced acute kidney injury.
Academic Article An mTOR kinase inhibitor slows disease progression in a rat model of polycystic kidney disease.
Academic Article A pan caspase inhibitor decreases caspase-1, IL-1a and IL-1?, and protects against necrosis of cisplatin-treated freshly isolated proximal tubules.
Academic Article Inhibition of autophagy increases apoptosis during re-warming after cold storage in renal tubular epithelial cells.
Academic Article NF-?B transcriptional inhibition ameliorates cisplatin-induced acute kidney injury (AKI).
Academic Article Protection Against Cold Storage-Induced Renal Tubular Cell Apoptosis.
Academic Article CD4 T cell knockout does not protect against kidney injury and worsens cancer.
Academic Article Protection From Apoptotic Cell Death During Cold Storage Followed by Rewarming in 13-Lined Ground Squirrel Tubular Cells: The Role of Prosurvival Factors X-Linked Inhibitor of Apoptosis and PhosphoAkt.
Grant Caspase-1 signaling in ischemic acute renal failure
Grant Mammalian target of rapamycin (mTOR) signaling in polycystic kidney disease (PKD)
Academic Article Catheter-based renal sympathetic denervation induces acute renal inflammation through activation of caspase-1 and NLRP3 inflammasome.
Concept Caspase Inhibitors
Academic Article Apoptosis and autophagy in polycystic kidney disease (PKD).

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