Associate Professor, Neurology and Neuroscience
Weill Cornell Medical College
Although stroke is a primary cause of disability and death in the U.S., there are few options for treating patients who have had a stroke. The paucity of treatment options has prompted the field to focus on identification and validation of potential targets for developing treatment strategies. While all these efforts have contributed to our understanding of stroke pathology, neuroprotective strategies that were effective in animal models or in vitro have not been successfully translated into clinical settings. Trained as a preclinical stroke modeler and in vivo physiologist, my laboratory closely examines stroke pathology and the gap between preclinical and clinical settings to evaluate the current status of this field.
Two main lines of research have been established in my laboratory; acute neuroprotection and long-term stroke recovery. For acute neuroprotective strategies, my laboratory has been examined several well known risk factors associated with higher incidence of vascular diseases and poor outcome. These include hypercholesterolemia, hypertension, diabetes, and obesity, and co-morbid conditions that have not been systematically examined in experimental animal models of stroke. In an effort to narrow the gap between animal models and clinical conditions, we proposed the inclusion of hyperlipidemia in our mouse model of stroke. In addition, close examination of stroke pathology revealed that multiple pro-death processes including inflammation, necrosis, apoptosis, oxidative stress, and vascular dysfunction are involved. Thus, targeting a specific pathway may not overcome the heterogeneous nature of stroke pathology. This led to the concept of a multi-modal approach: targeting a molecule that is involved in multiple pathogenesis, thereby simultaneously mitigating several pro-death pathways. To this end, we proposed that CD36, a class B scavenger receptor, is a potential target molecule for a multi-modal approach. We have been particularly focuses on in vivo phenomena and the underlying events by which peripheral inflammatory status influence the acute outcome of stroke-induced injury through a novel CD36 mechanism.
Equally important are the strategies that promote functional recovery. Since stroke-induced repair/remodeling largely occurs several weeks after stroke, strategies to promote the recovery processes have recently gained prospective attention. The ability to accommodate such plasticity in the post-stroke brain suggests the presence of intrinsic mechanisms to cope with insults and of targets that can be manipulated to improve stroke recovery. To this end, we have studied a role of brain-derived neurotrophic factor (BDNF), a widely expressed neurotrophin that plays a critical role in stroke recovery. Recently, a single nucleotide polymorphism (SNP) in the prodomain of bdnf that leads to substitution of methionine (met) for valine (val) at codon 66 (val66Met) has been identified. This variant, found only in humans, occurs with a frequency of 20-30% in Caucasians and up to 70% in Japanese and Chinese populations. The discovery of the common genetic variant of BDNF in human population provides an interesting research focus that lead to evaluate a potential role of BDNF-mediated angiogenesis/synaptogenesis on stroke outcome and recovery. By utilizing mice with genetic knock-in of the humanized bdnf variant in both allele (BDNFMet/Met) and wild type (BDNFVal/Val), my lab have been addressing the mechanisms by which BDNF contributes to stroke recovery. The proposed mechanistic and functional studies may potentially lead to translational approaches that aim at reversing a BDNF secretion deficit and downstream pathways to promote reparative processes for stroke patients with SNP.
Sunghee Cho received her B.S. in Chemistry at Yonsei University in Korea and M.S. in Nutrition at Cornell University. After she received her Ph.D. in Neuroscience/ Neurology from Weill Cornell Medical College, she did a post-doctoral fellowship (1993-1996), and was an instructor (1996-1998) and an assistant professor in the Department of Neurology/Neuroscience at Weill Cornell Medical College. She is currently an associate professor in the Department of Neurology/Neuroscience at Weill Cornell Medical College and a director of Preclinical Stroke Modeling at Burke Medical Research Institute. She is a member of the Society of Neuroscience, the International Society of Cerebral Blood Flow and Metabolism, American Heart/Stroke Association/ Member council on Stroke. Her stroke research has been supported by funding from National Institute of Health NHLBI, NCRR, American Heart Association, and Burke foundation.
“Recent Advances in Two-Photon Imaging: Technology Developments and Biomedical Applications”, Yu Chen, Hengchang Guo, Wei Gong, Luye Qin, Hossein Aleyasin, Rajiv R Ratan, Sunghee Cho, Jianxin Chen, and ShusenXie, Chinese Optics Letters, Vol. 11 (1), 011703, (Jan 10, 2013).
Cho S, Park E-M, Zhou P, Frys K, Ross EM, Iadecola C. (2005) Obligatory role of inducible nitric oxide synthase in ischemic preconditioning. J CBF & Metab 25:493-501
Park E-M, Cho BP, Volpe BT, Cruz MO, Joh TH, Cho S (2005) Ibuprofen protects ischemia-induced neuronal injury via up-regulating IL-1ra expression. Neuroscience 132:625-631
Cho S, Park E-M, Febbraio M, Anrather J, Park L, Racchumi G. Silverstein R, Iadecola, C. (2005) CD36, a scavenger receptor, mediates free radical production and tissue injury in cerebral ischemia. J Neuroscience 25:2504-2512
Park E-M, Cho S. (2006) Enhanced ERK-dependent CREB activation reduces apoptosis in staurosporine treated human neuroblastoma SK-N-BE(2)C cells. Neuroscience Letter 402:190-4
Park E-M, Cho S, Frys K, Glickstein S, Zhou P, Anrather J, Ross, M. E, Iadecola C (2006) Inducible nitric oxide synthase contributes to gender differences in ischemic brain injury. J CBF & Metab 26:392-401
Kawano T, Anrather J., Zhou P, Park L, Wang G, Frys K, KunzA, Cho S, Oria M, Iadecola C (2006) Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity. Nature Medicine 12(2):1-5
Cho S*, Szeto H.H., Kim E., Kim H., Tolhurst A.T., Pinto T.P. (2007) A novel cell permeable antioxidant peptide, SS31, attenuates ischemic brain injury by down-regulating CD36. J Biol Chem 282(7):4634-4642
( *corresponding author)
Langley B, D'Annibale MA, Suh K, Ayoub I, Tolhurst A, Bastan B, Yang L, Ko B, Fisher M, Cho S, Beal MF, Ratan RR. (2008) Pulse inhibition of histone deacetylases induces complete resistance to oxidative death in cortical neurons without toxicity and reveals a role for cytoplasmic p21(waf1/cip1) in cell cycle-independent neuroprotection. J Neuroscience 2;28(1):163-76. PMCID: PMC2577229
Kim E, Tolhurst AT, Qin LY, Chen XY, Febbraio M, Cho S (2008) CD36/fatty acid translocase, an inflammatory mediator, is involved in hyperlipidemia-induced exacerbation in ischemic brain injury. J Neuroscience. 30;28(18):4661-70 PMCID: PMC2830708
Shin JA, Park E-M, Choi J-S, Seo S-M, Lee J, Kang L, Lee K-E, Cho S (2009) Ischemic preconditioning-induced neuroprotection is associated with differential expression of IL-1β and IL-1 receptor antagonist in the ischemic cortex. J Neuroimmunology 217:14-19 PMCID:PMC2916648
Bao Y, Kim E, Bhosle S, Mehta H, Cho S (2010) A role for spleen monocytes in post-ischemic brain inflammation and injury J Neuroinflammation 7:92 PMCID:PMC3016273
Qin L, Kim E, Ratan R, Lee F, Cho S (2011) Genetic variant of BDNF (Val66Met) SNP attenuates stroke-induced angiogenic responses by enhancing CD36 expression. J Neuroscience 31(2):775-783
Park L, Wang G, Zhou P, Zhou J, Pitstic R, Previti M, Younkin Lm YounkinS, van Nostrand W, Cho S, Anrather J, Carlson G, Iadecola C (2011) The scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-β. Proc. Natl Acad Sci USA 108(12):5063-8. PMCID:PMC3064396
Zhou P, Qian L, D’Aurelio M, Cho S, Wang G, Manfredi G, Pickel V, Iadecola C (2012) Prohibitin reduces mitochondrial free radical production and protects brain cells from different injury modalities. J Neuroscience 11;32(2):583-92.
Bao Y, Qin L, Kim E, Bhosle S, Guo H, Febbraio M, Haskew-Layton RE, Ratan R, Cho S (2012) CD36 is involved in astrocyte activation and astroglial scar formation. J Cereb Blood Flow Metab. 32(8):1567-77.
Basso M, Berlin J, Xia L, Sama S, Ko B, Haskew-Layton R, Kim E, Antonyak M, Cerione R, Lismaa S, Willis D, Cho S, Ratan R. (2012) Transglutaminase inhibition protects against oxidative stress-induced neuronal death downstream of pathological ERK activation. J Neuroscience 9;32(19):6561-9.
Bao Y, Wang L, Xu Y, Yang Y, Wang L, Si S, Cho S*, Hong B* (2012) Salvianolic acid B inhibits macrophage uptake of modified low density lipoprotein (mLDL) in a scavenger receptor CD36-dependent manner. Atherosclerosis 223(1):152-9.
( *co-corresponding authors)
Kim E, Febbraio M, Bao Y, Tolhurst AT, Epstein JF, Cho S (2012) CD36 in the periphery and brain synergizes in stroke injury in hyperlipidemia. Annals of Neurology 71(6):753-64
Book Chapter /Review
Iadecola, C., Cho S, G. Feuerstein, and J. Hallenbeck (2004) Cerebral ischemia and Inflammation In Stroke: Pathophysiology, Diagnosis, and Management. J. P. Moore, D. Choi, J.C. Grotta, B. Weir and P.A. Wolf, Eds., Churchill Livingstone, NY, pp883-894
Ratan RR, Siddiq A, Smirnova N, Karpisheva K, Haskew-Layton R, McConoughey S, Langley B, Estevez A, Huerta PT, Volpe B, Roy S, Sen CK, Gazaryan I, Cho S, Fink M, LaManna J. (2007) Harnessing hypoxic adaptation to prevent, treat, and repair stroke.
J Mol Med 85(12):1331-8.
Cho S, Kim E (2009) CD36: A multi-modal target for acute stroke therapy. J Neurochemistry 1:126-132
Cho S (2012) CD36 as a therapeutic target for endothelial dysfunction in stroke. Current Pharmaceutical Design 18(25):3721-30
National Institute of Health NHBLI R01HL082511-06
Role of CD36 in ischemic inflammation and injury
National Institute of Health NS077897
Impact of BDNF SNP on stroke-induced plasticity and motor function
Role of CD36 in ischemic inflammation and injury
Stroke-induced brain injury has been viewed mainly from a neurocentric perspective, with much attention given to the primary injury site and its penumbra. However, an important notion derived from recent studies, including our own, favor a view that the peripheral inflammatory state influences the outcome of primary injury. The goal of this proposal is to investigate the mechanism(s) by which peripheral immunity may be regulated by cerebral ischemia and how this contributes to CNS damage in stroke. Specifically, we propose that spleen monocytes play a critical role in stroke-mediated injury through a novel CD36 mechanism. Stroke induces infiltration of peripheral monocytes into primary injury sites. The monocyte trafficking is a tightly controlled event that involves sequential recruitment of monocyte subsets that either express or do not express the pro-inflammatory chemokine receptor CCR2. Hyperlipidemia expands the CCR2+ monocyte subset in the spleen and accelerates the progression of cardio- and cerebrovascular diseases. We recently made an exciting observation that links the spleen to stroke pathology. We investigate the role of spleen monocytes in stroke-induced brain injury in hyperlipidemic conditions and underlying mechanism by which the process occurs. Specific projects include 1) determination of the role of spleen CCR2+ monocytes in injury following stroke, 2) if CD36 regulates CCR2 monocyte trafficking to infarct, and 3) utilizing several approaches to inhibit CD36 to achieve protection. Understanding of peripheral monocyte influence on the primary injury may open the door to the therapeutic application of neuro-immune modulation for stroke and a host of inflammatory diseases.
2. Long-term stroke recovery
Impact of BDNF SNP on stroke-induced plasticity and motor function
As stroke induces structural plasticity and behavioral adaptation, strategies that promote functional recovery following stroke have gained prospective attention. Brain-derived neurotrophic factor (BDNF) plays a critical role in CNS repair and plasticity. A single nucleotide polymorphism (SNP) of the prodomain of the bdnf gene occurs with high frequency in humans. However, the effect of this SNP on CNS recovery has been controversial. The current proposal addresses this controversy by investigating the extent to which BDNF SNP impacts motor recovery following stroke using mice that contain humanized SNP in both alleles (BDNFMet/Met) or one allele (BDNF+/Met). Hypotheses to be tested are 1) the BDNFMet allele promotes motor recovery via effects in the contralateral striatum, 2) the BDNFMet allele induces synaptic changes and changes in excitatory and inhibitory synaptic balance, and 3) whether CD36, an inflammatory receptor, mediate the process. The importance of the projects lies in that the studies will provide a means to predict the course of stroke recovery relevant to BDNF SNP carriers. In addition, defining a critical window for activating the CD36 pathway may lead to therapeutic strategies for promoting motor recovery in stroke patients who do not carry the SNP.