Faculty

Pioneering Rehabilitation

Rajiv R. Ratan, M.D., Ph.D.

Executive Director, Burke Medical Research Institute

Professor, Neurology and Neuroscience

Associate Dean

Weill Cornell Medical College

Phone:

(914) 597-2851

Research Focus

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).

Biography

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. 

Publications

Citations via PubMed


Selected Publications since 2009

Ma TC, Barco A, Ratan RR, Willis DE. cAMP-responsive Element-binding Protein (CREB) and cAMP Co-regulate Activator Protein 1 (AP1)-dependent Regeneration-associated Gene Expression and Neurite Growth. J Biol Chem. 2014 Nov 21;289(47):32914-25. doi: 10.1074/jbc.M114.582460. Epub 2014 Oct 8.

Bourassa MW, Ratan RRThe interplay between microRNAs and histone deacetylases in neurological diseases. Neurochem Int. 2014 Nov;77:33-9. doi: 10.1016/j.neuint.2014.03.012. Epub 2014 Mar 27.

Sleiman SF, Olson DE, Bourassa MW, Karuppagounder SS, Zhang YL, Gale J, Wagner FF, Basso M, Coppola G, Pinto JT, Holson EB, Ratan RRHydroxamic acid-based histone deacetylase (HDAC) inhibitors can mediate neuroprotection independent of HDAC inhibition. J Neurosci. 2014 Oct 22;34(43):14328-37. doi: 10.1523/JNEUROSCI.1010-14.2014.

Aleyasin H, Karuppagounder SS, Kumar A, Sleiman S, Basso M, Ma T, Siddiq A, Chinta SJ, Brochier C, Langley B, Haskew-Layton R, Bane SL, Riggins GJ, Gazaryan I, Starkov AA, Andersen JK, Ratan RRAntihelminthic Benzimidazoles Are Novel HIF Activators That Prevent Oxidative Neuronal Death via Binding to Tubulin. Antioxid Redox Signal. 2014 Aug 7. [Epub ahead of print]

Kumar A, Vaish M, Ratan RRTranscriptional dysregulation in Huntington's disease: a failure of adaptive transcriptional homeostasis. Drug Discov Today. 2014 Jul;19(7):956-62. doi: 10.1016/j.drudis.2014.03.016. Epub 2014 Mar 21.

Qin L, Jing D, Parauda S, Carmel J, Ratan RR, Lee FS, Cho S. An adaptive role for BDNF Val66Met polymorphism in motor recovery in chronic stroke. J Neurosci. 2014 Feb 12;34(7):2493-502. doi: 10.1523/JNEUROSCI.4140-13.2014.

Guo H, Aleyasin H, Dickinson BC, Haskew-Layton RE, Ratan RRRecent advances in hydrogen peroxide imaging for biological applications. Cell Biosci. 2014 Oct 27;4(1):64. doi: 10.1186/2045-3701-4-64. eCollection 2014. Review.

Alim I, Haskew-Layton RE, Aleyasin H, Guo H, Ratan RRSpatial, temporal, and quantitative manipulation of intracellular hydrogen peroxide in cultured cells. Methods Enzymol. 2014;547:251-73. doi: 10.1016/B978-0-12-801415-8.00014-X.

Guo H, Aleyasin H, Howard SS, Dickinson BC, Lin VS, Haskew-Layton RE, Xu C, Chen Y, Ratan RRTwo-photon fluorescence imaging of intracellular hydrogen peroxide with chemoselective fluorescent probes. J Biomed Opt. 2013 Oct;18(10):106002. doi: 10.1117/1.JBO.18.10.106002.

Basso M, Sleiman S, Ratan RRLooking above but not beyond the genome for therapeutics in neurology and psychiatry: epigenetic proteins and RNAs find a new focus. Neurotherapeutics. 2013 Oct;10(4):551-5. doi: 10.1007/s13311-013-0225-2. No abstract available.

Elder J, Cortes M, Rykman A, Hill J, Karuppagounder S, Edwards D, Ratan RRThe epigenetics of stroke recovery and rehabilitation: from polycomb to histone deacetylases. Neurotherapeutics. 2013 Oct;10(4):808-16. doi: 10.1007/s13311-013-0224-3. Review.

Basso M, Ratan RRTransglutaminase is a therapeutic target for oxidative stress, excitotoxicity and stroke: a new epigenetic kid on the CNS block. J Cereb Blood Flow Metab. 2013 Jun;33(6):809-18. doi: 10.1038/jcbfm.2013.53. Epub 2013 Apr 10. Review.

Brochier C, Dennis G, Rivieccio MA, McLaughlin K, Coppola G, Ratan RR, Langley B. Specific acetylation of p53 by HDAC inhibition prevents DNA damage-induced apoptosis in neurons. J Neurosci. 2013 May 15;33(20):8621-32. doi: 10.1523/JNEUROSCI.5214-12.2013.

Haskew-Layton RE, Payappilly JB, Xu H, Bennett SA, Ratan RR15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) protects neurons from oxidative death via an Nrf2 astrocyte-specific mechanism independent of PPARγ. J Neurochem. 2013 Feb;124(4):536-47. doi: 10.1111/jnc.12107. Epub 2013 Jan 3.

Ma TC, Langley B, Ko B, Wei N, Gazaryan IG, Zareen N, Yamashiro DJ, Willis DE, Ratan RRA screen for inducers of p21(waf1/cip1) identifies HIF prolyl hydroxylase inhibitors as neuroprotective agents with antitumor properties. Neurobiol Dis. 2013 Jan;49:13-21. doi: 10.1016/j.nbd.2012.08.016. Epub 2012 Aug 27.

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). 

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.

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.

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 ExpressionJ Neurosci. 2011 Jan 12;31(2):775-83.

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 miceActa Neurpathol. 2011 Apr;121(4):487-98. Epub 2010 Dec 16. 

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.

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 RRInhibition  of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease. EMBO Mol Med. 2010 Sep;2(9):349-70.

Ratan RR. 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.

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.

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.

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 diseaseAntioxid Redox Signal 12, 435-443. 

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.     

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. 

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.

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 USA 106,19599-19604.

Ratan RR. (2009) Epigenetics and the nervous system: epiphenomenon or missing piece of the neurotherapeutic puzzle? Lancet Neurol 8, 975-977.

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. 

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.

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. 

Ratan RR & Noble M. Novel multi-modal strategies to promote brain and spinal cord injury recovery. Stroke 2009;40;S130-S132.

Current Projects

Marietta Zille, Ph.D.
mzille@burke.org
maz3003@med.cornell.edu
(914) 368-3104

Determining Cell Death Mechanisms after Experimental Hemorrhagic Stroke In Vitro and In Vivo
Intracerebral hemorrhage (ICH) accounts for about 15% of all strokes and has the highest mortality rates among strokes with up to 50% within 30 days after the insult. It is known to increase intracranial pressure and is associated with excitotoxicity, oxidative stress, and inflammation. However, the mechanisms of how cells die after ICH remain unclear. In the lab, I systematically investigate cell death mechanisms using hemin- and hemoglobin-induced toxicity in cultured primary cortical neurons and cell lines as well as using the collagenase model of ICH in vivo. Core techniques employed are manifold including live/dead assays, viral transfections, microfluidics, microscopy, western blotting, PCR, stereotactic surgery, transgenic animals as well as behavioral testing.  A better understanding of the pathophysiology of ICH will allow for the development of new treatment strategies that can be tested in the lab and the rehabilitation hospital.


Megan Bourassa, Ph.D.
mbourassa@burke.org
meb3002@med.cornell.edu
(914) 368-3121

Histone deacetylases inhibitors for neurotherapeutics
Histone deaceytlase (HDAC) inhibitors are a promising therapeutic of neurological diseases. My research focuses on using HDAC inhibitors to block neurodegeneration and promote neurorepair. The acetylation of histone proteins increases gene expression, and by blocking the removal of acetyl groups, HDAC inhibitors elevate histone acetylation. As a result of HDAC inhibition, a large transcriptional response occurs, which appears to enhance neuronal survival. I am interested in identifying which of the 11 Zn-dependent HDACs are most critical in order to promote the ideal gene expression profile for neuronal survival. I am also investigating the effects of diet on the production of endogenous HDAC inhibitors. Specifically, I am interested in how dietary interventions can be used to treat neurological diseases, including Alzheimer’s disease and stroke.


Amit Kumar, Ph.D.
akumar@burke.org
amk3001@med.cornell.edu
(914) 368-3120

The human brain represents only 2% of the body weight but it utilizes around 20% of total body glucose. This shows how crucial glucose metabolism is for the proper functioning of neurons and other cell types in the brain. Classically, glucose has been viewed mainly as an important fuel source for energy intensive process of neuronal activity. But a closer analysis shows that glucose metabolism in the brain is not so simple and may have many other regulatory functions than just as an energy source. Various cell types of the brain express different specific glucose transporters, which enable them to regulate their glucose metabolism in a very individualized manner. This raises the possibility that glucose metabolism in the brain may have other important physiological relevance as well in specific cell types with different physiology. Considering these broader possibilities, I am interested in understanding the regulatory involvement of glucose metabolism in other vital functions of the brain such as redox balance, neuronal plasticity, long-term potentiation, and learning and memory. My further interest is to understand the metabolic sensing of genes involved in neuronal plasticity. As a part of developing a translational understanding of brain glucose metabolism, my research is also focused towards exploring the adaptive and maladaptive consequences of defects in glucose metabolism in Alzheimer’s disease which is seen years before we see any other visible symptoms such as tangles/plaques deposition and memory deficits, etc., in AD patients. It will enable us to find out the key therapeutics targeting specific arms of this pathway, which could not only increase neuroprotection but also enhance neuronal plasticity. Classically, lactate was considered a fuel source only under anaerobic conditions. But many recent findings have established that lactate serves as an important fuel source for neurons even under aerobic conditions. In the light of recent scientific findings, the regulatory role of lactate in the brain seems to be much broader than just an energy source. I am deeply interested in understanding the regulatory involvement of lactate in certain vital functions of neurons other than energy production.


Ishraq Alim, Ph.D.
ialim@burke.org
isa3001@med.cornell.edu
(914) 368-3190

Disruptive strategies to understand the role(s) of reactive oxygen species in physiology and disease
Oxidative stress is an event associated with a variety of neurological disorders, including stroke. It occurs when neurons are unable to maintain reactive oxygen species (ROS) homeostasis. Clinical trials using chemical antioxidants targeting ROS to treat both ischemic and hemorrhagic stroke have thus far failed, suggesting ROS plays a complex role in cellular function. My interest is to understand specific cellular events that are associated with oxidative stress leading to neuronal death. I have developed an in vitro model using destabilization domains (dd; developed by Thomas Wandless at Stanford University) fused to known antioxidant enzymes to finely regulate their expression in cultured neurons. Using this model in cells under oxidative stress conditions, I can differentiate ROS-induced events that cause cell death from those that do not. This strategy will help in understanding the complex role of ROS in cellular function and potentially identify specific therapeutic targets that are involved in oxidative stress.  


Saravanan S. Karuppagounder, Ph.D.
SARAVANA@burke.org
Ssk2004@med.cornell.edu
(914) 597-2696 

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.

Funding

National Institutes of Health P01 AG14930-10
"Mitochondrial Dysfunction in Neurogeneration of Aging:
Modulation of genes involved in mitochondrial adaptation (Project 1)."
Dates of project: 05/01/2010 – 04/30/2015
The major goals of this project are to define the role of transglutaminase as a selective corepressor.
Role: Project Leader (PI: Gibson)  

Adelson Foundation
"Pharmacological and Molecular Activation of Adaptive Programs Associated with Neural Protection and Repair."
Dates of project: 09/01/2010 - 08/31/2012
The major goal of this project is to elucidate and utilize mechanisms of neural protection and repair in stroke and spinal cord injury.
Role: Principal Investigator  

The Dana Foundation 08121738
"Blood Brain Marker Development for Prognosis on Recovery from Stroke."
Dates of project: 06/01/2008 – 05/31/2012
The major goals of this project are to identify blood biomarkers in humans for recovery from stroke, TBI or Spinal Cord Injury.
Role: Principal Investigator 

Thomas Hartman Foundation
"Investigation of the Efficacy and Mechanism of FDA approved Activators of Hypoxic Adaptation in the Metabolic Consequences and Treatment of Parkinson’s Disease."
Dates of project: 06/01/2009 – 12/31/2011 for Parkinson’s Research, Inc.
The major goal of this project is to evaluate the effects of HIF prolyl hydroxylase inhibitors in Parkinson's disease models.
Role: Principal Investigator  

Intl Rett Syndrome Foundation
"Novel Screening Assays to Develop Better Therapeutics for Rett Syndrome."
Dates of project: 10/01/2010 - 09/3/2011
The major goal of this project is to utilize several highly vetted and druggable libraries to define novel therapeutics for Rett Syndrome.
Role: Principal Investigator  

Laboratory

Current Lab Members:

Ishraq Alim, Postdoctoral Fellow

Megan Bourassa, Postdoctoral Fellow

Saravanan S. Karuppagounder, Instructor

Amit Kumar, Postdoctoral Fellow

Marietta Zille, Postdoctoral Fellow