Results Through Rehabilitation & Research
Professor, Neurology and Neuroscience
Weill Cornell Medical College
The central focus of the Ratan laboratory is to understand adaptive programs (post-transcriptional and transcriptional) that facilitate the brain’s ability to combat injury and to foster repair. While the main focus of the lab is stroke (ischemic and hemorrhagic) and spinal cord injury, our studies span many different diseases including Huntington’s disease, Parkinson’s disease, and Rett Syndrome. Since its inception in 1994, the laboratory has utilized an in vitro model of oxidative stress to understand the precise mechanisms by which disrupted redox homeostasis leads to death in neurons. This simple model system, which harnesses the experimental leverage of primary neurons in cell culture, has spawned a large number of exciting projects in the lab and projects targeted by progeny of the lab. While stress is primarily sensed in most cells including neurons in the cytoplasm, the major attention of the lab has been on the nucleus. Our global hypothesis is that disease is a failure of compensation, and better understanding of how the nervous system adapts to injury with a particular focus on epigenetic modulators (HDACs, transglutaminase, MecP2) and transcription factors (Sp1, CREB, HIF-1alpha) as well as enzymes that modulate the stability of these factors (HIF prolyl hydroxylases).
Rajiv (“Raj”) Ratan received his B.A. in Neuroscience (Magna Cum Laude) from Amherst College in 1981 and received the John Woodruff Simpson Fellowship in Medicine. He completed an M.D. and Ph.D. at the New York University School of Medicine where he graduated as a member of AOA in 1988. He completed his Ph.D. with Dr. Michael Shelanski (Chair of Pathology at Columbia University) and Dr. Frederick Maxfield (Chair of Biochemistry at Cornell) where he focused on novel methods to monitor calcium gradients in living cells. He completed an Internship in Medicine at the University of Chicago and was a Neurology resident and then Chief Resident in Neurology at Johns Hopkins (1991-1992). He was awarded the Jay Slotkin Award for excellence in research while a resident; and subsequently received the Passano Foundation Clinician Scientist Award while completing a fellowship in Neurorehabilitation and a post-doc in the Department of Neuroscience at Hopkins. In 1994, he was promoted to Assistant Professor of Neurology and Rehab Medicine at Hopkins and he started his own lab with the help of his post-doc mentor, Jay Baraban. In 1996, he was recruited to set up the Neuroprotection Laboratory in the Department of Neurology and Program in Neuroscience at Harvard Medical School (Harvard Institutes of Medicine and Beth Israel Hospital). He became an Associate Professor at Harvard in 1999. In 2002, Dr. Ratan moved to Burke to Direct the Research Institute. He was formally appointed the Winifred Masterson Burke Professor of Neurology and Neuroscience at Weill Medical College in 2004 and named an Associate Dean for the medical college in 2011.
“Recent Advances in Two-Photon Imaging: Technology Developments and Biomedical Applications”, Yu Chen, HengchangGuo, Wei Gong, Luye Qin, HosseinAleyasin, Rajiv R Ratan,Sunghee Cho, Jianxin Chen, and ShusenXie, Chinese Optics Letters, Vol. 11 (1), 011703, (Jan 10, 2013).
Ratan RR & Noble M. Novel multi-modal strategies to promote brain and spinal cord injury recovery. Stroke 2009;40;S130-S132.
McConoughey S, Niatsetskaya Z, Pasternack R, Hils M, Ratan RR, Cooper A, JL (2009) A non-radioactive dot-blot assay for transglutaminase activity. Anal Biochem. 390, 91-93.
Siddiq A, Aminova L, Troy C, Suh K, Messer Z, Semenza GL, and Ratan RR. (2009) Selective Inhibition of hypoxia-inducible factor (HIF) prolyl-hydroxylase 1 mediates neuroprotection against normoxic oxidative death via HIF- and CREB-independent pathways. J Neurosci. 29: 8828-8838.
Lee DW, Rajagopalan S, Siddiq A, Gwiazda R, Yang L, Beal MF, Ratan RR, Andersen JK.(2009) Inhibition of prolyl hydroxylase protects against 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity: model for the potential involvement of the hypoxia-inducible factor pathway in Parkinson disease. J Biol Chem 284, 29065-29076.
Ratan RR. (2009) Epigenetics and the nervous system: epiphenomenon or missing piece of the neurotherapeutic puzzle?, Lancet Neurol 8, 975-977.
Rivieccio MA, Brochier C, Willis DE, Walker BA, D’Anniable MA, McLaughlin K, Siddiq A, Kozikowski AP, Jeffrey SR, Twiss JL, Ratan RR, and Langley B. (2009) HDAC6 is a target for protection and regeneration following injury in the nervous system. Proc Natl Acad Sci U S A 106,19599-19604.
Sleiman SF, Basso M, Mahishi L, Kozikowski AP, Donohoe ME, Langley B, Ratan RR (2009) Putting the “HAT” back on survival signaling: the promises and challenges of HDAC inhibition in the treatment of neurological conditions. Expert Opin Invest Drugs 18, 573-584.
Gibson GE, Starkov A, Blass JP, Ratan RR and Beal MF. (2009) Cause and consequence: Mitochondrial dysfunction initiates and propagates neuronal dysfunction, neuronal death and behavioral abnormalities in age-associated neurodegenerative diseases. Biochim Biophys 2010 Jan;1802(1):122-34. Epub 2009 Aug 26 Review. PMID: 19715758 (PubMed – indexed for MEDLINE).
Ma TC, Campana A, Lange PS, Lee H-H, Banerjee K, Bryson J. Barney M, Lata A, Shabnam G, Roman J, Barnes S, Morris Jr SM, Willis DE, Twiss JL, Filbin MT, Ratan RR. (2010) A Large-Scale Chemical Screen for Regulators of the Arginase 1 Promoter Identifies the Soy Isoflavone Daidzein as a Clinically Approved Small Molecule That Can Promote Neuronal Protection or Regeneration via a cAMP-Independent Pathway. J Neurosci 30, 739-748.
Niatsetskaya Z, Basso M, Speer RE, McConoughey SJ, Coppola G, Ma TC, and Ratan RR .(2010) HIF prolyl hydroxylase inhibitors prevent neuronal death induced by mitochondrial toxins: therapeutic implications for Huntington’s disease and Alzheimer’s disease. Antioxid Redox Signal 12, 435-443.
Akiba Y, Cave JW, Akiba N, Langley B, Ratan RR and Baker H. (2010) Histone deacetylase inhibitors de-repress tyrosine hydroxylase expression in the olfactory blub and rostral migratory stream. Biochen Biophys Res Commun.
Smirnova NA, Rakhman I, Moroz N, Basso M, Payappilly J, Kazakov S, Hernandez-Guzman F, Gaisina, IN, Kozikowksi AP, Ratan RR and Gazaryan IG. Utilization of an in vivo reporter for high throughput identification of branched small molecule regulators of hypoxic adaptation. Chemistry & Biology. (2010), doi: 10.1016/j.chembiol. 2010.03.008.
Ratan RR (2010) Beyond Neuroprotection to Brain Repair: Exploring the Next Frontier in Clinical Neuroscience to Expand the Therapeutic Window for Stroke. Editorial, Transl. Stroke Res. (2010) 1:71-73
McConoughey SJ, Basso M, Niatsetskaya ZV, Sleiman SF, Smirnova NA, Langley BC, Mahishi L, Cooper AJ, Antonyak MA, Cerione RA, Li B, Starkov A, Chaturvedi RK, Beal MF, Coppola G, Geschwind DH, Ryu H, Xia L, lismaa SE, Pallos J, Pasternack R, Hills M, Fan J, Raymond LA, Marsh JL, Thompson LM, Ratan RR. Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease. EMBO Mol Med. 2010 Sep;2(9):349-70.
Haskew-Layton RE, Payappilly JB, Smirnova NA, Ma TC, Chan, Kelvin K, Murphy, Timothy H., Guo, Hengchang, Langley, Brett, Sultana, Rukhsana, Butterfield, D. Allan, Santagata, Sandro, Alldred, Melissa J, Gazaryan, Irina G, Bell, George W, Ginsberg, Stephen D, Ratan, Rajiv R. Controlled enzymatic production of astrocytic hydrogen peroxide protects neurons fromoxidative stress via an Nrf2-independent pathway. Proc Natl Acad Sci USA 2010 Oct 5;107-(40):17385-90. Epub 2010 Sep 20.
Lee J, Kosaras B, Del Signore SJ, Cormier K, McKee A, Ratan RR, Kowall NW, Rye H. Modulation of lipid peroxidation and mitochondrial function improves neuropathology in Huntington’s disease mice. Acta Neurpathol. 2011 Apr;121(4):487-98. Epub 2010 Dec 16.
Qin L, Kim E, Ratan RR, Lee FS, Cho S. Genetic Variant of BDNF (Val66Met) Polymorphism Attenuates Stroke-Induced Angiogenic Responses by Enhancing anti-Angiogenic Mediator CD36 Expression. J Neurosci. 2011 Jan 12;31(2):775-83.
Sleiman, SF, Langley BC, Basso M, Berlin J, Xia L, Payappilly JB, Kharel MK, Guo H, Marsh JL, Thompson LM, Mahishi L, Ahuja P, Maclellan WR, Geschwind DH,
Coppola G, Rohr J, Ratan RR. Mithramycin Is a Gene-Selective Sp1 Inhibitor That Identifies a Biological Intersection between Cancer and Neurodegeneration. J Neurosci.2011 May 4;31(18):6858-6870.
Smirnova NA, Haskew-Layton RE, Basso M, Hushpulian DM, Payappilly JB, Speer RE, Ahn YH, Rakhman I, Cole PA, Pinto JT, Ratan RR, Gazaryan IG. Development of neh2-luciferase reporter and its application for high throughput screening and real-time monitoring of nrf2 activators. Chem Biol.2011 June 24;18(6):752-65. PMID:21700211(PubMed – in process)
Friedreich Ataxia (FRDA): This most common inherited ataxia was first described by Dr.Nicholaus Friedreich in 1863. FRDA is an autosomal recessive neurodegenerative disease characterized by progressive gait and limb ataxia, sensory loss, muscle weakness, dysarthria, absent lower limb reflexes loss of the sense of position and vibration. Increased cardiac ventricular wall thickness is observed in all patients, with most (80%) developing a life-threatening hypertrophic cardiomyopathy. About 20% of patients exhibit increased incidence of diabetes mellitus / impaired glucose tolerance. Projects that I am currently undertaking include (1) Identify biomarkers (small RNAs) to follow the disease and treatment options in clinical trials (2) Understand Molecular Mechanisms of silencing in Friedreich ataxia and (3) Small molecule library screening to identify therapeutic compound.
Hossein Aleyasin, M.D., Ph.D.
My work in the lab has primarily focused on two areas:
1) The reactive oxygen species hydrogen peroxide (H2O2) is an integral signaling molecule, however little is known about how localized levels of H2O2within a cell affects H2O2’s biological role. To study the physiological role of H2O2we developed a system to enzymatically generate intracellular H2O2in specific cellular compartments in a highly controllable manner using the genetically modified Rhodotorula gracilis D-amino acid oxidase (DAAO), a yeast enzyme that metabolizes D-amino acids to the corresponding imino acid and produces H2O2as a byproduct. This tool will allow us to define how H2O2can act as a mediator or oxidative stressor by manipulating the physiological and pathological ranges of intracellular concentrations.
2) In collaboration with Dr. Prusky’s lab (visual physiology and neuroplasticity), we are developing an ischemic brain injury model to study how stroke may affect visual plasticity. The ultimate goal of this study is to setup an in vivo system for pre-clinical evaluation of the efficacy of small molecules to improve rehabilitation in stroke patients.
Transcriptional regulation is a hallmark of several neurodegenerative diseases. We have recently reported that transglutaminase 2 (TG2), an interesting enzyme with multiple activities, is a significant driver of transcriptional dysregulation in Huntington’s Disease and I am particularly interested in understanding how it exerts this function. The characterization of nuclear function of TG2 could lead to the development of therapies capable of suppressing nuclear TG2 activity and hence restore transcriptional homeostasis and prevent or halt progression of this devastating disease. I am additionally interested in better understanding the role of polyamines, TG2 substrates, in neurodegeneration and to uncover a novel function as modulators of transcription via TG2.
Renee E. Haskew-Layton, Ph.D.
Astrocytes are a major cell type in the brain and spinal cord that play a host of roles in the central nervous system including supporting the function, maintenance and survival of neurons. My interests in astrocyte biology coupled with the transcriptional regulation and oxidative stress expertise of the Ratan lab has lead to several exciting discoveries, namely identifying intracellular hydrogen peroxide and prostaglandin signaling in astrocytes as potent mediators of neuroprotection. Ongoing work, which is focused on elucidating the precise mechanisms involved in these astrocyte-dependent protective pathways, will aide in understanding how to best exploit the therapeutic potential of astrocytes in acute neurological and neurodegenerative disorders.
My research interests focus on the use of small molecule inhibitors of hypoxia inducible factor prolyl hydroxylases (HIF PHDs) as novel therapeutics for intracerebral hemorrhage. We have developed an in vitro model to mimic hemorrhagic stroke using hemin, which induces cell death in various neuronal cell types that is rescued by PHD inhibitors. We also utilize an in vivo rat or mice models for hemorrhagic stroke using autologous blood infusion or hemin. We are testing the efficacy of PHD inhibitors in these preclinical animal models using end points including brain edema volume, neuronal survival, and behavioral outcomes. Our findings suggest that PHD inhibitors are promising candidates for preventing cell death in hemorrhagic stroke.
Oncogenic transformation of post mitotic neurons triggers cell death, however the identity of genes critical for degeneration remain unclear. I am interested in identifying the transcriptional and post-transcriptional networks that reside at the intersection of cancer and neurodegeneration. Because many anti-tumor drugs such as Mithramycin A (MTM) and HDAC inhibitors are also neuroprotective, I am utilizing them as tools to decipher the pathways they affect. My studies identified several genes (Myc, c-Src, Hif1a, and p21waf1/cip1), involved in neoplastic transformation, whose altered expression correlates with neuroprotection. Currently, I am trying to understand how these genes exert their functions and whether their target downstream pathways are also common between cancer and neurodegeneration.
Hypoxia Inducible Factor (HIF) is a master regulator of the adaptive response to hypoxia. HIF coordinates a broad program of gene expression that favors cell survival in hypoxia by restoring blood supply, shifting metabolism, and reducing energy needs. Although HIF is clearly protective in hypoxia, it is unclear whether manipulating HIF signaling can promote neuronal survival in cerebral ischemia, or how HIF is regulated by important modulators of ischemic injury such as hypoglycemia and reactive oxygen species (ROS). The objective of my dissertation research is to determine how glucose and mitochondrial ROS production influence HIF in ischemic human neuronal cells. My broader research interests include cellular and molecular biology of neurological diseases and cancer.
Ongoing Research Support
P01 AG14930-10 (PI: Gibson) 05/01/2010 – 04/30/2015
Mitochondrial Dysfunction in Neurogeneration of Aging
Modulation of genes involved in mitochondrial adaptation (Project 1)
Role: Project Leader
The major goals of this project are to define the role of transglutaminase as a selective corepressor.
08121738 (PI: Ratan) 06/01/2008 – 05/31/2012
The Dana Foundation
Blood Brain Marker Development for Prognosis on Recovery from Stroke
The major goals of this project are to identify blood biomarkers in humans for recovery from stroke, TBI or Spinal Cord Injury.
Thomas Hartman Foundation (PI: Ratan) 06/01/2009 – 12/31/2011 for Parkinson’s Research, Inc.
Investigation of the Efficacy and Mechanism of FDA approved Activators of Hypoxic Adaptation in the Metabolic Consequences and Treatment of Parkinson’s Disease
The major goal of this project is to evaluate the effects of HIF prolyl hydroxylase inhibitors in Parkinson's disease models.
Intl Rett Syndrome Foundation (PI: Ratan) 10/01/2010 - 09/3/2011
Novel Screening Assays to Develop Better Therapeutics for Rett Syndrome
The major goal of this project is to utilize several highly vetted and druggable libraries to define novel therapeutics for Rett Syndrome.
Adelson Foundation (PI: Ratan) 09/01/2010 - 08/31/2012
Pharmacological and Molecular Activation of Adaptive Programs Associated with Neural Protection and Repair.
The major goal of this project is to elucidate and utilize mechanisms of neural protection and repair in stroke and spinal cord injury.
Li Xia (Shelley), Lab Manager
Manuela Basso, Instructor
Lata Mahishi, Instructor
Sama F. Sleiman, Instructor
Hossein Aleyasin, Postdoctoral Fellow
Saravanan S. Karuppagounder, Postdoctoral Fellow
Rachel Speer, Graduate Student