Cleveland Clinic Lerner Research Institute

Cleveland, OH, United States

Cleveland Clinic Lerner Research Institute

Cleveland, OH, United States

The Cleveland Clinic Lerner Research Institute is home to all laboratory-based, translational and clinical research at the Cleveland Clinic.The Institute comprises 11 Departments: Biomedical Engineering, Cancer Biology, Cell Biology, Genomic Medicine Institute, Immunology, Molecular Cardiology, Molecular Genetics , Neuroscience, Pathobiology, Quantitative Health science, and Stem Cell Biology and Regenerative Medicine.More than 1,300 work at the Institute, including about 200 Principal Investigators who have laboratory space. Its Staff members also participate in the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University and the Molecular Medicine PhD Program. In 2008, the Institute had a total research budget of $258 million . More than 260 Postdoctoral Fellows and 170 Graduate Students continued their professional development. Research by the Staff appeared in nearly 1,300 journal manuscripts, books or book chapters. The Institute's Chair is Paul E. DiCorleto, PhD, who was named to the position in 2002. He is the fifth Chair since the Institute was founded in 1945. Wikipedia.


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Obermeier B.,Cleveland Clinic Lerner Research Institute | Daneman R.,University of California at San Francisco | Ransohoff R.M.,Cleveland Clinic Lerner Research Institute
Nature Medicine | Year: 2013

The interface between the blood circulation and the neural tissue features unique characteristics that are encompassed by the term 'blood-brain barrier' (BBB). The main functions of this barrier, namely maintenance of brain homeostasis, regulation of influx and efflux transport, and protection from harm, are determined by its specialized multicellular structure. Every constituent cell type makes an indispensable contribution to the BBB's integrity. But if one member of the BBB fails, and as a result the barrier breaks down, there can be dramatic consequences and neuroinflammation and neurodegeneration can occur. In this Review, we highlight recently gained mechanistic insights into the development and maintenance of the BBB. We then discuss how BBB disruption can cause or contribute to neurological disease. Finally, we examine how this knowledge can be used to explore new possibilities for BBB repair. © 2013 Nature America, Inc.


Sossey-Alaoui K.,Cleveland Clinic Lerner Research Institute
Seminars in Cell and Developmental Biology | Year: 2013

WAVE3 belongs to the WASP/WAVE family of actin cytoskeleton remodeling proteins. These proteins are known to be involved in several biological functions ranging from controlling cell shape and movement, to being closely associated with pathological conditions such as cancer progression and metastasis. Last decade has seen an explosion in the literature reporting significant scientific advances on the molecular mechanisms whereby the WASP/WAVE proteins are regulated both in normal physiological as well as pathological conditions. The purpose of this review is to present the major findings pertaining to how WAVE3 has become a critical player in the regulation of signaling pathways involved in cancer progression and metastasis. The review will conclude with suggesting options for the potential use of WAVE3 as a therapeutic target to prevent the progression of cancer to the lethal stage that is the metastatic disease. © 2012 Elsevier Ltd.


Fiocchi C.,Cleveland Clinic Lerner Research Institute
Digestive Diseases | Year: 2012

To discuss a cure for IBD, one should first define the concept 'a cure'. If it is intended as the general restoration of health, this is already possible, as many current therapies do a good job in inducing long periods of remission in Crohn's disease, and colectomy can technically cure ulcerative colitis. If it is more strictly defined as the complete and permanent elimination of the cause, predisposing and permissive factors, reinstatement of normal microbial ecology and restoration of mucosal immune homeostasis, then a cure for IBD is out of reach, at least for now. Regardless of the definition, major strides have been made in attempting to cure IBD by addressing the key components of its pathogenesis: the environment (exposome), the genetic makeup (genome), the gut microbiota (microbiome) and the immune system (immunome). However, the isolated modulation of each component is insufficient to provide a cure, and different requirements may be needed depending on the stage of the disease and each patient subset. To achieve a cure, one key approach is currently missing: the integration of knowledge from all the pathogenic components. We continue to learn more and more about each component using traditional 'canonical' systems, which allow the accumulation of data without taking into consideration the other components. We are still not studying the 'omes' of IBD, we should be using 'omics' technologies that can generate a more global vision of IBD pathogenesis on which to base novel, multiple pathway-integrated therapies. Copyright © 2012 S. Karger AG, Basel.


de la Motte C.A.,Cleveland Clinic Lerner Research Institute
American Journal of Physiology - Gastrointestinal and Liver Physiology | Year: 2011

The causes of fibrosis, or the inappropriate wound healing, that follows chronic intestinal inflammation are not well defined and likely involve the contributions of multiple cellular mechanisms. As other articles in this series confirm, inflammatory cytokines clearly play a role in driving cell differentiation to the myofibroblast phenotype, promoting proliferation and extracellular matrix deposition that are characteristic of fibrotic tissue. However, controlling the balance of cytokines produced and process of myofibroblast differentiation appears to be more complex. This review considers ways in which hyaluronan, an extracellular matrix component that is remodeled during the progression of colitis, may provide indirect as well as direct cues that influence the balancing act of intestinal wound healing. © 2011 by the American Physiological Society.


Fiocchi C.,Cleveland Clinic Lerner Research Institute
Digestive Diseases | Year: 2014

The complexity of IBD is well recognized as are the putative four major components of its pathogenesis, i.e. environment, genetic makeup, gut microbiota and mucosal immune response. Each of these components is extremely complex on its own, and at present should be more appropriately defined by the terms 'exposome', 'genome', 'microbiome' and 'immunome', respectively, based on the 'ome' suffix that refers to a totality of some sort. None of these 'omes' is apparently capable of causing IBD by itself; it is instead the intricate and reciprocal interaction among them, through the so-called 'IBD interactome', that results in the emergence of IBD, or more appropriately the 'IBD integrome'. To deal with and understand such overwhelming biological complexity, new approaches and tools are needed, and these are represented by 'omics', defined as the study of related sets of biological molecules in a comprehensive fashion, such as genomics, transcriptomics, proteomics, metabolomics, and so on. Numerous bioinformatics-based tools are available to explore and take advantage of the massive amount of information that can be generated by the analysis of the various omes and their interactions, aiming at identifying the molecular interactome underlying any particular status of health and disease. These novel approaches are fully applicable to IBD and allow us to achieve the ultimate goal of developing and applying personalized medicine and far more effective therapies to individual patients with Crohn's disease and ulcerative colitis. For the practicing gastroenterologist, an omics-based delivery of healthcare may be intimidating, but it must be accepted and implemented if he or she is to provide the best possible care to IBD patients. © 2014 S. Karger AG, Basel.


Dasarathy S.,Cleveland Clinic Lerner Research Institute
Digestive Diseases and Sciences | Year: 2013

Liver transplantation is believed to reverse the clinical and metabolic abnormalities of cirrhosis. Reduced skeletal muscle mass or sarcopenia contributes to increased mortality and adverse consequences of cirrhosis. Failure of reversal of sarcopenia of cirrhosis after liver transplantation is not well recognized. Six temporally, geographically, and methodologically distinct follow-up studies in 304 cirrhotics reported conflicting data on changes in indirect measures of skeletal muscle mass after transplantation. Distinct measures of body composition but not skeletal muscle mass were used and did not focus on the clinical consequences of sarcopenia after transplantation. A number of studies reported an initial rapid postoperative loss of lean mass followed by incomplete recovery with a maximum follow-up of 2 years. Posttransplant sarcopenia may be responsible for metabolic syndrome and impaired quality of life after liver transplantation. Potential reasons for failure to reverse sarcopenia after liver transplantation include use of immunosuppressive agents [mammalian target of rapamycin (mTOR) and calcineurin inhibitors] that impair skeletal muscle growth and protein accretion. Repeated hospitalizations, posttransplant infections, and renal failure also contribute to posttransplant sarcopenia. Finally, recovery from muscle deconditioning is limited by lack of systematic nutritional and physical-activity-based interventions to improve muscle mass. Despite the compelling data on sarcopenia before liver transplantation, the impact of posttransplant sarcopenia on clinical outcomes is not known. There is a compelling need for studies to examine the mechanisms and consequences of sarcopenia post liver transplantation to permit development of therapies to prevent and reverse this disorder. © 2013 Springer Science+Business Media New York.


McIntyre T.M.,Cleveland Clinic Lerner Research Institute
Biochimica et Biophysica Acta - Biomembranes | Year: 2012

This report reviews structurally related phospholipid oxidation products that are biologically active where molecular mechanisms have been defined. Phospholipids containing polyunsaturated fatty acyl residues are chemically or enzymatically oxidized to phospholipid hydroperoxides, which may fragment on either side of the newly introduced peroxy function to form phospholipids with a truncated sn-2 residue. These truncated phospholipids not subject to biologic control of their production and, depending on the sn-2 residue length and structure, can stimulate the plasma membrane receptor for PAF. Alternatively, these chemically formed products can be internalized by a transport system to either stimulate the lipid activated nuclear transcription factor PPARγ or at higher levels interact with mitochondria to initiate the intrinsic apoptotic cascade. Intracellular PAF acetylhydrolases specifically hydrolyze truncated phospholipids, and not undamaged, biosynthetic phospholipids, to protect cells from oxidative death. Truncated phospholipids are also formed within cells where they couple cytokine stimulation to mitochondrial damage and apoptosis. The relevance of intracellular truncated phospholipids is shown by the complete protection from cytokine induced apoptosis by PAF acetylhydrolase expression. This protection shows truncated phospholipids are the actual effectors of cytokine mediated toxicity. This article is part of a Special Issue entitled: Oxidized phospholipids - their properties and interactions with proteins. © 2011 Elsevier B.V. All rights reserved.


Brown J.M.,Cleveland Clinic Lerner Research Institute | Hazen S.L.,Cleveland Clinic Lerner Research Institute
Current Opinion in Lipidology | Year: 2014

Purpose of Review: Atherosclerosis and associated cardiovascular disease (CVD) remains the leading cause of mortality in Western societies. It is well accepted that the consumption of foods abundant in saturated fats and cholesterol, like meats, egg yolk and high-fat dairy products, are associated with increased CVD risk. New evidence suggests that trimethylamine (TMA)-containing nutrients within these foods, including phosphatidylcholine, choline, and L-carnitine, can enter into a microbial metabolic pathway that promotes CVD. In this review, we highlight the role of gut microbiota-driven nutrient metabolism as a novel pathway promoting CVD. RECENT FINDINGS: Recent studies demonstrate a link between ingestion of dietary phosphatidylcholine, choline, and L-carnitine and CVD risk. At the center of this pathway is gut microbiota-dependent synthesis of a metabolic intermediate called TMA, and subsequent host-driven conversion of TMA to trimethylamine-N-oxide (TMAO). Microbiota-dependent generation of TMAO is associated with increased risk of incident major adverse cardiovascular events in humans, and provision of TMAO promotes atherosclerosis in mice. SUMMARY: Microbial metabolism of TMA containing nutrients can lead to formation of the proatherogenic compound TMAO. Recent insights into this diet-microbe-host interaction provide new clues surrounding the pathogenesis of atherosclerosis, and may serve as a framework for new CVD therapies. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Bhattaram P.,Cleveland Clinic Lerner Research Institute
Nature communications | Year: 2010

During organogenesis, neural and mesenchymal progenitor cells give rise to many cell lineages, but their molecular requirements for self-renewal and lineage decisions are incompletely understood. In this study, we show that their survival critically relies on the redundantly acting SoxC transcription factors Sox4, Sox11 and Sox12. The more SoxC alleles that are deleted in mouse embryos, the more severe and widespread organ hypoplasia is. SoxC triple-null embryos die at midgestation unturned and tiny, with normal patterning and lineage specification, but with massively dying neural and mesenchymal progenitor cells. Specific inactivation of SoxC genes in neural and mesenchymal cells leads to selective apoptosis of these cells, suggesting SoxC cell-autonomous roles. Tead2 functionally interacts with SoxC genes in embryonic development, and is a direct target of SoxC proteins. SoxC genes therefore ensure neural and mesenchymal progenitor cell survival, and function in part by activating this transcriptional mediator of the Hippo signalling pathway.


Ransohoff R.M.,Cleveland Clinic Lerner Research Institute | Cardona A.E.,Cleveland Clinic Lerner Research Institute
Nature | Year: 2010

A microglial cell is both a glial cell of the central nervous system and a mononuclear phagocyte, which belongs to the haematopoietic system and is involved in inflammatory and immune responses. As such, microglia face a challenging task. The neurons of the central nervous system cannot divide and be replenished, and therefore need to be protected against pathogens, which is a key role of the immune system, but without collateral damage. In addition, after physical injury, neural cells need restorative support, which is provided by inflammatory responses. Excessive or chronic inflammatory responses can, however, be harmful. How microglia balance these demands, and how their behaviour can be modified to ameliorate disorders of the central nervous system, is becoming clear. © 2010 Macmillan Publishers Limited. All rights reserved.

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