Cleveland Clinic Lerner Research Institute
The Lerner Research Institute is home to all laboratory-based, translational and clinical research at Cleveland Clinic. Our mission is to understand the underlying causes of human diseases and to develop new treatments and cures. We are an integrated research community consisting of numerous departments and centers. [More: About Us]
News Releases:
- 10/08/2009: Dr. Silverman's lab in the department of Cancer Biology has co-authored a study that was published online in Science. The new research raises the possibility that the XMRV virus, previously linked to Prostate Cancer, may be a contributing factor in the pathogenesis of Chronic Fatigue Syndrome. For more information, see the Cleveland Clinic's news release.
Disease-oriented Research
Investigators work in basic, translational and clinical research. A hallmark of the Institute is its focus on disease-oriented research. The approach blends the research across several Departments and disciplines to address major areas. Contact information and detailed descriptionsUs of the research programs can be found in the Faculty Directory. Investigators are also listed by the following disease categories: allergic and immunologic, cancer, cardiovascular, eye, infectious diseases, metabolic, musculoskeletal, and neurologic.
- Cell Biology: EPRS and Translation. In Molecular Cell [Impact Factor 12.903], Paul Fox, PhD, and colleagues reported new findings showing that "IFN-gamma-induced, two-kinase mediated, dual-site phosphorylation of EPRS at Ser886 and Ser999 in the noncatalytic linker domain controls multiple events required for GAIT-mediated gene-silencing activity." The team observed that Ser999 phosphorylation directs the formation of a functional GAIT complex that binds initiation factor eIF4G and represses translation. They write that EPRS "gchoreographs the time-dependent behavior of the GAIT complex in response to IFN-gamma" and that "EPRS phosphorylation is unique among multisite phosphotargets in that sequential phosphorylation of two sites by a single stimulus induces at least five distinct responses involving interactions with three GAIT complex proteins and an RNA structural element and also facilitates the interaction of L13a with eIF4G." [See Arif A, et al. Two-site phosphorylation of EPRS coordinates multimodal regulation of noncanonical translational control activity. Mol Cell 2009 Jul 31;35:164-180.]
- Cell Biology: Unexpected Function of eIF4a3 in Selenium Deficiency. In Molecular Cell [Impact Factor 12.903], Donna Driscoll, PhD, and coauthors report that their data "support a model in which eIF4a3 links selenium status with differential selenoprotein expression." They found "an unexpected function of eIF4a3 in selectively regulating selenoprotein mRNA translation. During the initial stages of selenium deficiency, changes in the translational profile of the selenoproteome must occur rapidly to preserve the expression of selenoproteins with essential functions. Thus, binding of eIF4a3 to a subset of selenoprotein mRNAs could act as a brake to create a temporary translational arrest for those nonessential stress-related selenoproteins. Upon restoration of the selenium status, the translational repression of these selenoproteins could be alleviated promptly..." An accompanying commentary notes that the article demonstrates that "the selective translation of selenocysteine-containing proteins can be regulated by the mutually exclusive binding of eIF4a3 and SECIS binding protein 2 ... to a cis-acting element in the 3' untranslated region ... of the target mRNA." [See Budiman ME, et al. Eukaryotic initiation factor 4a3 is a selenium-regulated RNA-binding protein that selectively inhibits selenocysteine incorporation. Mol Cell 2009 Aug 28;35:479-89.]
- Molecular Cardiology: PPAR and Diabetes. In The Lancet [Impact Factor 28.409], A. Michael Lincoff, MD, and coauthors report that Phase II studies of some 330 patients from seven countries who received the trial drug aleglitazar (a peroxisome proliferator-activated receptor agonist) found it to be "safe and well tolerated" over the 16 weeks of the study. The authors state: "Recruitment of patients with acute coronary syndromes and type 2 diabetes into a large, long-term, phase III trial for the secondary prevention of cardiovascular morbidity and mortality will begin in February, 2010, to further establish the safety and efficacy of this promising new agent." The accompanying Commentary discusses aleglitazar and other drugs with cautious optimism for the larger trial to come. [See Henry RR, et al. Effect of the dual peroxisome proliferator-activated receptor-alpha/gamma agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, dose-ranging study. Lancet 2009 Jul 11;374:126-135.]
- Quantitative Health Sciences: Caution about PFO Repair. In JAMA [Impact Factor 31.718], Eugene Blackstone, MD, and coauthors reviewed intraoperative transesophageal echocardiograms (TEEs) of more than 13,000 Cleveland Clinic patients undergoing surgery from 1995 through 2006; these patents had comorbidities, but had not previously been diagnosed with patent foramen ovale (PFO) or atrial septal defect. TEEs done intraoperatively happened to identify (apparently benign) PFOs in 17% of patients in this population and most were repaired when found. The data showed that patients with PFO had similar rates of inhospital death and postoperative stroke as those without PFO. The team concluded that "[i]ncidental PFO is common in patients undergoing cardiothoracic surgery but is not associated with increased perioperative morbidity or mortality." However, they recommend caution and more rigorous study of the trend towards repair of these PFOs: "The finding that repair may increase postoperative stroke risk should discourage routine surgical closure and foster further investigation to delineate whether there is any benefit in terms of long-term stroke prevention and which patients might benefit from this intervention.." [See Krasuski RA, et al. Prevalence and repair of intraoperatively diagnosed patent foramen ovale and association with perioperative outcomes and long-term survival. JAMA 2009 Jul 15;302:290-297.]
- Cell Biology: Pediatric Liver Disease. Ariel Feldstein, MD, and a multicenter group of investigators recently reported in Hepatology [Impact Factor 10.734] their findings on how nonalcoholic steatohepatitis and nonalcoholic fatty liver disease may differ in adults vs. children. Investigators from 5 institutions studied data from 130 children seen over 12 years to compare patterns of liver injury, extent of fibrosis, and other factors. Although some features of adult and pediatric types of the disease overlapped, the investigators found that "[s]erum aspartate aminotransferase levels were the only clinical or laboratory data that independently predicted severity of fibrosis (P = 0.003)" and they were able to identify "histological lesions associated with progressive disease." [See Carter-Kent C, et al. Nonalcoholic steatohepatitis in children: A multicenter clinicopathological study. Hepatology 2009 Jun 19; Epub ahead of print.]
From another study, this one seeking data on survival and outcomes over the long term in 66 children affected with nonalcoholic fatty liver disease, Dr. Feldstein and colleagues discussed their findings in Gut [Impact Factor 10.015]. Within this group monitored over a long period, disease progressed; two children died and two had liver transplant procedures because of cirrhosis (one of these latter patients developed NAFLD again and underwent a second transplant). The children’s survival without a donated liver was "significantly shorter in the NAFLD cohort as compared to the expected survival in the general United States population of the same age and sex…," the authors found.
- Immunology: Face Transplantation. The widely publicized milestone of Maria Siemionow, MD, PhD, and colleagues was recently detailed in The Lancet [Impact Factor 28.638]. The article describes the rationale and innovative procedures for the "tailored composite tissue allograft" for the woman who became the first U.S. patient to receive a near total (80%) face transplant. The patient had undergone 23 "conventional" reconstructive surgeries with autologous grafts prior to transplant. The authors note that attention was given to "immunosuppressive therapy, psychological and ethical outcomes, and re-integration of the patient into society." Interestingly, the donor was of blood type AB and the recipient type A. Evidence of tissue rejection occurred by day 47 post transplant, but "a single bolus of corticosteroids reversed rejection." At 6 months, "the functional outcome has been excellent. In contrast to her status before transplantation, the patient can now breathe through her nose, smell, taste, speak intelligibly, eat solid foods, and drink from a cup." Acknowledging the many ethical and medical considerations involved in patient selection, the authors opine that face transplantation "should be taken into consideration as an early option, if only to spare a patient years of continued disfigurement, social ostracism, and the cumulative financial burden of multiple reconstructions." [See Siemionow M, et al. Near-total human face transplantation for a severely disfigured patient in the USA. Lancet 2009 Jul 18;374:203-209]
Dr. Siemionow also recently coauthored a review article with French colleagues that considers the application of extracorporeal photopheresis (ECP, sometimes called "photochemotherapy") as a supplementary therapy for tissue/organ rejection in cases of face, hand, and other transplantations and for graft-vs.-host disease after bone marrow or stem cell transplantations. The authors address "the mechanisms of action for ECP, including the induction of peripheral lymphocyte apoptosis, the modifi cation of cytokine patterns, and the activation of regulatory T-cells [and] the indications of ECP in transplantation, with emphasis on its implementation to composite tissue allotransplantations. [See Hivelin M, et al. Extracorporeal photopheresis: From solid organs to face transplantation. Transpl Immunol 2009 Jul;21:117-128.
- In a report published in the May 2009 issue of Developmental Cell [Impact Factor 12.436], Paul Fox, PhD, Linda Graham, MD, and colleagues report on the roles of actin and profilin in cell migration. They found that "local regulation of thymosin-beta4 (Tbeta4) binding to actin monomer (G-actin) coordinates actin polymerization with metalloproteinase synthesis to promote endothelial cell motility." An unexpected finding was "diminished interaction between Tbeta4 and G-actin at the cell leading edge despite their colocalization there." In assessing the many mechanisms required to make cells move, the authors state: "[Profilin] induces polarized dissociation of [the actin-Tbeta4] complex resulting in G-actin availability at the leading edge of a motile [endothelial cell]. The spatially restricted dissociation process enhances cell movement by simultaneously promoting actin polymerization and inducing formation of a ternary [Tbeta4]–ILK–Akt2 complex which induces [matrix metalloproteinase-2] synthesis. These findings provide a new mechanism for coordination of actin polymerization and matrix degradation during cell migration." [See Fan Y, Gong Y, Ghosh PK, Graham LM, Fox PL. Spatial coordination of actin polymerization and ILK-Akt2 activity during endothelial cell migration. Dev Cell 2009 May;16:661-74.
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