Raghu Vemuganti Research Laboratory

 

Principal Investigator

 

     

Raghu Vemuganti, PhD

Associate Professor

Department of Neurological Surgery

H4/334 Clinical Science Center

600 Highland Avenue

Madison WI 53792

Phone: 608-263-4055 Fax: 608-263-1728

Email: vemugant@neurosurg.wisc.edu

Vemuganti CV

 

Lab Members

 
Ashutosh Dharap, MS
(PhD in Progress)
a.dharap@neurosurg.wisc.edu

  


Venkata Nakka, PhD
Research Associate
v.nakka@neurosurg.wisc.edu



Gopal Pandi, PhD
Research Associate
g.pandi@neurosurg.wisc.edu

  
   

 

Courses

 

 

Research Projects

 

 

Role of Endoplasmic Reticulum Stress after Tramatic Brain Injury
Traumatic brain injury (TBI) is one of the leading causes of death and disability, worldwide. TBI leads to multiple, distinct overlapping cell signaling pathways which may regulates either cell survival/damage. Consistent with the role of ER stress in many pathophysiological conditions of the brain, we are focusing to study the effect of ER stress in the progression of secondary brain damage after TBI. Our long-term goal includes the inhibition of ER stress in combination with Oxidative stress, one of the major modes of cell death. Thus, our studies may help in elucidating the mechanisms underlying the TBI and may further help in establishing a possible ER targeted therapeutic strategies in combination with the oxidative stress in the treatment of TBI.

Role of ISG15 after Cerebral Ischemia
Interferon Stimulated Gene-15 (ISG15), a 17-kDa ubiquitin-like molecule, contains two ubiquitin domains, including a carboxy-terminal LRLRGG motif, through which it forms conjugates with target proteins, a process known as ISGylation (Lai et al. 2009). Activation of this pathway results in the conjugation of ISG15 to over 100 known target proteins that may plays a major role in the regulation of multiple biological pathways. Our preliminary data suggested that cerebral ischemia/reperfusion injury results in increased ISGylation of high molecular weight proteins in the cortex and striatum of rats. Currently, we are studying the effect of ISGylation after focal cerebral ischemia in the mice lacking ISG15, which may provide a better insight to establish therapeutic strategies aiming at stroke.
Lai C, Struckhoff JJ, Schneider J, Martinez-Sobrido L, Wolff T, García-Sastre A, Zhang DE, Lenschow DJ (2009) Mice lacking the ISG15 E1 enzyme UbE1L demonstrate increased susceptibility to both mouse-adapted and non-mouse-adapted influenza B virus infection. J Virol. 1147–1151

Role of MicroRNAs in Cerebral Ischemia
MicroRNAs are 18-25 nucleotide-long, non-coding RNAs that control cellular function by either degrading cellular RNA or arresting their translation. Recently we have shown that a number of microRNAs are up-regulated and down-regulated during transient focal ischemia in the adult rodent brain (Dharap et al., 2009). Currently, we are studying the role of these altered microRNAs in the post-ischemic pathophysiological cascade, identifying their targets and exploring the influence of epigenetic mechanisms on their expression patterns. Ultimately, our studies aim to provide a fresh insight into the cellular and molecular mechanisms of an ischemic stroke, and identify potential targets for pharmacological therapy.

 

JAK-STAT-SOCS signaling in post-ischemic cerebral inflammation         

When induced, SOCS family of proteins controls cytokine production by negative feedback regulation of JAK-STAT pathways. We observed increased expression of SOCS3 and activation of STAT3 in the post-ischemic brain. As cytokines promote inflammation and neuronal damage, we are evaluating the mechanism of action of ischemia-induced SOCS3 by using antisense, RNAi and adenoviral vectors. To identify the complete complement of genes down-stream to SOCS3 signaling, we are conducting GeneChip analysis following knockdown and overexpression of specific proteins of SOCS/STAT pathway.

 

Role of transcription factors Egr1 and C/EBPβ in cerebral inflammation

The molecular mechanisms of inflammatory progression in brain are not well understood. We observed increased expression of the transcription factors Egr1 and C-EBPβ after focal ischemia and hypothesize that these two start the pro-inflammatory cascades in brain. We are currently analyzing the functional significance, down-stream effectors and the interactive mechanism of action of Egr1 and C-EBPβ in controlling the post-ischemic cerebral inflammation using knockout mice, adenoviruses and antisense. 

 

Therapeutic potential of PPAR-g agonists in controlling cerebral inflammation

PPAR are ligand-activated transcription factors known to control lipid metabolism, glucose metabolism and inflammation. Thiozolinediones rosiglitazone and pioglitazone acts as potent exogenous agonists of PPAR-g and we are currently trying to understand if these compounds minimize cerebral inflammation following stroke and if yes, what is their molecular mechanism of action.

 

Gene expression profiling following CNS Injury 

Acute CNS insults alter the expression of several genes with significant functional consequences. To develop a viable therapy, it is essential to identify and understand the role of the novel molecular pathways affected by an insult. My laboratory recently conducted a massive gene expression profiling following focal cerebral ischemia, traumatic brain injury and spinal cord injury. These studies identified inflammatory gene expression driven by pro-inflammatory transcription factors as a common molecular mechanism underlying excitotoxic pathologies. We use microarrays and proteomics to identify novel therapeutic targets to develop neuroprotective drugs. 

 

Stem cell proliferation after Stroke

Our lab showed that stroke stimulates neural progenitor cell proliferation in adult rats. As increasing neurogenesis in the post-ischemic brain has tremendous potential to replace lost neurons, we are studying if growth factors promote post-ischemic survival and differentiation of the neural progenitor cells.

 

Research Funding

 

·         Transcription Factors & Inflammatory Mediators in Stroke                        NIH RO1

        01/2003 to 01/2008                 Principal Investigator                                     

·         Neurogenesis after stroke: effect of growth factors                                      NIH RO1

        01/2003 to 01/2006                 Co-Investigator

·         Role of Egr-1 in Post-ischemic Inflammation and Brain Damage            NIH RO1

        01/2006 to 01/2010                 Principal Investigator                                             

·         Therapeutic Potential of PPAR-γ agonists in Stroke Neuroprotection     American Heart Assoc.

        07/2005 to 06/2007                 Principal Investigator

·         Folic Acid Enhances Repair Mechanism in the Adult CNS                       NIH RO1

        01/2006 to 01/2010                 Co-Investigator

·         Role of Inflammatory Mediators in Ischemic Neuronal Damage             American Heart Assoc.

        01/2003 to 01/2004                 Principal Investigator

·         Inflammatory Control in Preventing Stroke-induced Neuronal Death      American Heart Assoc.

        01/2003 to 01/2005                 Principal Investigator                                     

·         Role of Polyamines in Neuroplasticity after Cerebral Ischemia                American Heart Assoc.

        01/2001 to 01/2003                 Co-Investigator

·         Chronic spinal cord injury and neuropathic pain                                         UW Med School

        05/2004 to 04/2005                 Co-investigator

·         Glutamate transporter function following focal ischemia                           American Heart Assoc.

        07/1999 to 06/2002                 Principal Investigator

·         Ornithine Decarboxylase and Ischemic Brain Edema                                NIH RO1

        04/1998 to 03/2000                 Co-Investigator

·         Polyamines and neuroplasticity after cerebral ischemia                            American Heart Assoc.

        07/2001 to 06/2003                 Co-Investigator

·         Glutamate transporter and transient focal ischemia                                   American Heart Assoc.

        07/1998 to 06/2000                 Principal Investigator

·         Role of glutamate transporters in transient global ischemia                      UW Med School

        04/1998 to 03/1999                 Principal Investigator

 

Representative Publications (click on the journal name for the PDF)

 

·         Dharap A, Bowen K, Place R, Li LC, Vemuganti R (2009) Transient focal ischemia induces extensive temporal changes in rat cerebral MicroRNAome. J Cereb Blood Flow Metab (Online early).

·         Vemuganti R. (2008) Therapeutic potential of PPAR-gamma activation in stroke. PPAR Res In press.

·         Tureyen K, Brooks N, Bowen K, Svaren J, Vemuganti R (2008) Transcription Factor Early Growth Response-1 Induction Mediates Inflammatory Gene Expression and Brain Damage following Transient Focal Ischemia. J Neurochem 105: 1313-1324.

·         Kapadia R, Yi JH, Vemuganti R. (2008) Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists. Front Biosci 13:1813-26, 2008.

·         Park S, Yi J, Satriotomo I, Miranpuri G, Bowen K, Resnick DK, Vemuganti R  (2007) Treatment with PPAR-g ligands decrease spinal cord injury induced neuronal damage, apoptosis, neurological dysfunction and inflammation. J Pharm Exp Therap 320:1002-1012.

·         Wiltrout C, Lang B, Yan Y, Dempsey RJ, Vemuganti R (2007) Repairing brain after stroke: A review on post-ischemic neurogensis. Neurochem Int 50:1028-1041.

·         Yi JH, Park SW, Kapadia R, Vemuganti R (2007) Role of transcription factors in mediating post-ischemic cerebral inflammation and brain damage:  A review. Neurochem Int 50:1014-1027.

·         Yan Y, Sailor K, Lang B, Park SW, Vemuganti R, Dempsey RJ (2007) MCP1 plays a critical role in neuroblast migration following focal cerebral ischemia. J Cereb Blood Flow Metab 27:1213-1224.

·         Tureyen K, Kapadia R, Bowen KK, Satriotomo I, Liang J, Feinstein DL, Vemuganti R (2007) Peroxisome proliferator-activated receptor-γ agonists induce neuroprotection following transient focal ischemia in normotensive, normoglycemic as well as hypertensive and type-2 diabetic rodents. J Neurochem 101:41-56.

·         Kapadia R, Tureyen K, Bowen KK, Kalluri H, Johnson PF, Vemuganti R (2006) Decreased brain damage and curtailed inflammation in transcription factor C/EBP-β knockout mice following transient focal cerebral ischemia. J Neurochem 98:1718-1731

·         Satriotomo I, Bowen KK, Vemuganti R (2006) JAK2 and STAT3 Activation Contributes to Neuronal Damage Following Transient Focal Cerebral Ischemia. J Neurochem 98:1253-1368

·         Vemuganti R, Dempsey RJ (2006) Increased expression of genes that control ionic homeostasis, 2nd messenger signaling & metabolism in carotid plaques from symptomatic stroke patients. J Neurochem 97:2-96

·         Vemuganti R, Kalluri H, Ye S, Hazell AS (2006) Microarray analysis reveals gene expression changes associated with inflammation, cellular stress, and structural damage in the thalamus and inferior colliculus following oxidative impairment in experimental Wernicke's encephalopathy. Eur J Neurosci 23:1172-1188

·         Yan Y, Sailor KS, Vemuganti R, Dempsey RJ (2006) Insulin like growth factor-1 is an endogenous mediator of focal ischemia-induced neural progenitor proliferation. Eur J Neurosci 24:45-54

·         Bowen KK, Naylor M, Vemuganti R (2006) Prevention of inflammation is a mechanism of preconditioning-induced neuroprotection against focal cerebral ischemia. Neurochem Int 49:127-35

·         Vemuganti R, Carson MJ (2006) Cerebral inflammation: How homeland defense is handled in the CNS. Neurochem Int 49:105

·         Naylor M, Bowen KK, Sailor KA, Dempsey RJ, Vemuganti R (2005) Preconditioning-induced ischemic tolerance stimulates growth factor expression and neurogenesis in adult rat hippocampus. Neurochem Int 47:565-572

·         Vemuganti R, Dempsey RJ (2005) Carotid atherosclerotic plaques from symptomatic patients share molecular fingerprints to develop in a neoplastic fashion: A microarray study. Neuroscience 131:359-374 Additional data

·         Vemuganti R, Dempsey RJ, Bowen KK (2004) Inhibition of ICAM-1 expression by antisense oligonucleotides is neuroprotective after middle cerebral artery occlusion. Stroke 35:179-184

·         Dhodda VK, Sailor KA, Vemuganti R (2004) Putative Endogenous Mediators of Preconditioning-Induced Ischemic Tolerance in Rat Brain Identified by Genomic and Proteomic Analysis. J Neurochem 89:73-89

·         Dempsey RJ, Sailor K, Bowen K, Tureyen K, Vemuganti R (2003) Stroke-induced progenitor cell proliferation in adult spontaneously hypertensive rat brain: Effect of exogenous IGF-1 and GDNF. J Neurochem 87:586-597

·         Vemuganti R, Dhodda V, Song G, Bowen KK, Dempsey RJ (2003) Traumatic Brain Injury-Induced Acute Gene Expression Changes in Rat Cerebral Cortex Identified by GeneChip Analysis. J Neurosci Res 71:208-219

·         Vemuganti R, Bowen KK, Dhodda V, Song G, Franklin J, Dempsey RJ (2002) Microarray analysis of the gene expression changes in rat brain after focal ischemia. J Neurochem 83:1072-1086

·         Vemuganti R, Dogan A, Todd KG, Bowen KK, Kim B-T, Rothstein JD, Dempsey RJ (2001) Antisense knockdown of the glial glutamate transporter GLT-1, but not neuronal glutamate transporter EAAC1, exacerbates focal cerebral ischemia-induced neuronal damage. J Neurosci 21:1876-1883

·         Vemuganti R, Dogan A, Rao AM, Bowen KK, Hatcher J, Dempsey RJ (2001) Knockdown of ODC exacerbates ischemic neuronal damage. J Cereb Blood Flow Metab 21:945-954

·         Vemuganti R, Dogan A, Bowen KK, Todd KG, Dempsey RJ (2001) Antisense knockdown of the glial glutamate transporter GLT-1 exacerbates hippocampal neuronal damage following traumatic injury to rat brain. Eur J Neurosci 13:119-128

·         Song G, Cechvala C, Resnick DK, Dempsey RJ, Vemuganti R (2001) GeneChip analysis after acute spinal cord injury in rat. J Neurochem 79: 804-815

 

 

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Last update: 9/11/09