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	Gunasingh Jeyaraj, PhD I was born in Nazareth, a small blessed city in Tamil Nadu, India. This city was developed by a Christian missionary by name Dr. Arthur Margoschis. I completed my masters and doctoral studies at the University of Madras, India. Through my postdoctoral training I became interested in the development of novel therapeutics for neurodegenerative diseases. In this cutting-edge research, I successfully executed several projects as a postdoctoral researcher. I approached this biomedical research using different biophysical techniques, molecular cloning, viral transfections, primary neuronal cultures and transgenic mouse models. I was interested in the ongoing project on the therapeutic and neuroprotective properties of glutamate receptor antagonists in Parkinson’s disease funded by the National Parkinsons Foundation in the Smith Lab. It involves studying novel promising preclinical therapeutic approaches for Parkinson’s disease (PD) which urged me to become part of this research team on basal ganglia and movement disorders. The primary goal of my project is to assess the neuroprotective properties of a specific metabotropic gluatamte receptor antagonist called MTEP on MPTP (1-methyl 4-phenyl 1,2,3, tetrahydropyridine) induced neurodegeneration of midbrain dopaminergic neurons in monkey models of Parkinson’s disease. MPTP intoxication in monkeys is the gold standard model for studying PD. This model can reproduce not only the destruction of the nigrostriatal DA system but also results in almost the entire myriad of motor symptoms characteristic of parkinsonism. PD is the second most common neurodegenerative disorder, affecting more than one million Americans. The pathology is related to dopamine (DA) depletion in the basal ganglia, a consequence of degeneration of dopaminergic neurons located in the substantia nigra pars compacta (SNc). This eventually reduces the dopaminergic output to the striatum which leads to an imbalance in the basal ganglia circuitry, thereby, resulting in the motor abnormalities seen in PD patients (ie slowness of movements, rigidity, gait problems etc…). Increased glutamatergic transmission of specific connections in the basal ganglia circuits is thought to be a key pathophysiological feature of PD. This led various research teams to test the antiparkinsonian effects of glutamate receptor antagonists in animal models of PD or in PD patients. However, because of side effects induced by broad spectrum glutamate receptor compounds, these studies did not result in suitable therapies that could be used in humans. The ideal therapy would alleviate motor symptoms, prevent dopaminergic cell death and have limited side effects. We believe that a new group of glutamate receptors, called G protein-coupled metabotropic glutamate receptors (mGluRs), which are heavily distributed in the basal ganglia, might be an alternative targets to modulate glutamate hyperactivity in PD. This gave the insight to test the novel mGluR5 antagonist MTEP, which has a greater affinity and specificity for mGluR5 than other antagonists. To validate our goal I am using the following approaches. In vitro positron emission tomography (PET) imaging offers the opportunity for the early detection of dopamine depletion in the striatum and SNc. 18F-ECNT, a dopamine transporter (DAT) specific radioligand used for the PET study. The monkey motor behaviour is assessed by automated infrared beams breaks and pressing one of eight buttons on a keypad each time the monkey moves it arms, legs, head, or torso while monitoring from the next room. Monkeys are trained in a food retrieval task. The monkey is basically required to retrieve a raisin from a device that uses infrared beams to automatically measure the time required for the monkey to move its hand from the door to the raisin and from the raisin back to the door. A modified Universal Parkinson’s Disease Rating Scale is used to rate Parkinsonism in the monkeys. A computerized stereological toolbox software program (stereo investigator) is used to estimate the total number of dopaminergic cells in SNc, on the basis of optical fractionator method. Subcellular and subsynaptic localization of glutamate receptors in different nuclei of basal ganglia will be analysed using electron microscope. PD biomarkers like TH, DAT, calbindin and acetylcholine are examined using immunohistochemistry. Our preliminary PET study shows that MTEP monotherapy significantly protects dopaminergic neurons from the toxic MPTP insult thereby preventing DAT occupancy reduction and the parkinsonian motor symptoms when compared with control monkeys. In addition, MTEP monotherapy showed a modest acute anti-akinetic effect in MPTP monkeys. Further studies arein the process to defined reproducibility and accuracy of the therapeutic approach. I thoroughly enjoy the intellectual and technical challenges of research and the friendly environment in my lab. I believe we may reveal a milestone therapy for PD patients. Publications E. Philip Jesudason, B’Joe Baben, Ashok BS, J. Gunasingh Masilamoni, R. Kirubagaran, W. Charles E. Jebaraj & R. Jayakumar. Anti-inflammatory effect of melatonin on Aβ vaccination in mice. Molecular and Cellular Biochemistry 2007, 298, 69-81. J. Gunasingh Masilamoni, E. Philip Jesudason, Bjoe, Charles E. Jebaraj & R. Jayakumar. The molecular chaperone a-crystallin protects inflammation-induced neurodegeneration. .Biochim Biophys Acta - Molecular Basis of Disease, 2006, 1762, 284 - 291. J. Gunasingh Masilamoni, Vignesh, R. Kirubagaran, E. Philip Jesudason & R. Jayakumar. The neuroprotective efficacy of a-crystallin against acute inflammation in mice. Brain Research Bulletin 2005, 67 235-241. J. Gunasingh Masilamoni, E. Philip Jesudason, S. Nirmala Bharathi and R. Jayakumar. The protective effect of a-crystallin against acute inflammation in mice.Biochim Biophys Acta - Molecular Basis of Disease, 2005, 1740, 411-420. J. Gunasingh Masilamoni, E. Philip Jesudason, K. Samuel Jesudoss, J. Murali, Solomon FD Paul & R. Jayakumar. Role of fibrillar Ab25-35 in the inflammation induced rat model with respect to oxidative vulnerability. Free Radical Research 2005 39 603–612. E. Philip Jesudason, J. Gunasingh Masilamoni, R. Kirubagaran, G. Dicky John Davis and R. Jayakumar. The protective role of DL-a-lipoic acid in biogenic amines catabolism triggered by Aß amyloid vaccination in mice. Brain Research Bulletin. 2005, 65, 361-367. E. Philip Jesudason, J. Gunasingh Masilamoni, K. Samuel Jesudoss, & R. Jayakumar The protective role of DL a-Lipoic acid in the oxidative vulnerability triggered by Ab amyloid vaccination in mice. Molecular Cellular Biochemistry. 2005, 270, 29-37.

Gunasingh Jeyaraj, PhD

I was born in Nazareth, a small blessed city in Tamil Nadu, India. This city was developed by a Christian missionary by name Dr. Arthur Margoschis. I completed my masters and doctoral studies at the University of Madras, India. Through my postdoctoral training I became interested in the development of novel therapeutics for neurodegenerative diseases. In this cutting-edge research, I successfully executed several projects as a postdoctoral researcher. I approached this biomedical research using different biophysical techniques, molecular cloning, viral transfections, primary neuronal cultures and transgenic mouse models.

I was interested in the ongoing project on the therapeutic and neuroprotective properties of glutamate receptor antagonists in Parkinson’s disease funded by the National Parkinsons Foundation in the Smith Lab. It involves studying novel promising preclinical therapeutic approaches for Parkinson’s disease (PD) which urged me to become part of this research team on basal ganglia and movement disorders.

The primary goal of my project is to assess the neuroprotective properties of a specific metabotropic gluatamte receptor antagonist called MTEP on MPTP (1-methyl 4-phenyl 1,2,3, tetrahydropyridine) induced neurodegeneration of midbrain dopaminergic neurons in monkey models of Parkinson’s disease. MPTP intoxication in monkeys is the gold standard model for studying PD. This model can reproduce not only the destruction of the nigrostriatal DA system but also results in almost the entire myriad of motor symptoms characteristic of parkinsonism. PD is the second most common neurodegenerative disorder, affecting more than one million Americans. The pathology is related to dopamine (DA) depletion in the basal ganglia, a consequence of degeneration of dopaminergic neurons located in the substantia nigra pars compacta (SNc). This eventually reduces the dopaminergic output to the striatum which leads to an imbalance in the basal ganglia circuitry, thereby, resulting in the motor abnormalities seen in PD patients (ie slowness of movements, rigidity, gait problems etc…). Increased glutamatergic transmission of specific connections in the basal ganglia circuits is thought to be a key pathophysiological feature of PD. This led various research teams to test the antiparkinsonian effects of glutamate receptor antagonists in animal models of PD or in PD patients. However, because of side effects induced by broad spectrum glutamate receptor compounds, these studies did not result in suitable therapies that could be used in humans. The ideal therapy would alleviate motor symptoms, prevent dopaminergic cell death and have limited side effects. We believe that a new group of glutamate receptors, called G protein-coupled metabotropic glutamate receptors (mGluRs), which are heavily distributed in the basal ganglia, might be an alternative targets to modulate glutamate hyperactivity in PD. This gave the insight to test the novel mGluR5 antagonist MTEP, which has a greater affinity and specificity for mGluR5 than other antagonists.

To validate our goal I am using the following approaches.

In vitro positron emission tomography (PET) imaging offers the opportunity for the early detection of dopamine depletion in the striatum and SNc. 18F-ECNT, a dopamine transporter (DAT) specific radioligand used for the PET study.
The monkey motor behaviour is assessed by automated infrared beams breaks and pressing one of eight buttons on a keypad each time the monkey moves it arms, legs, head, or torso while monitoring from the next room.
Monkeys are trained in a food retrieval task. The monkey is basically required to retrieve a raisin from a device that uses infrared beams to automatically measure the time required for the monkey to move its hand from the door to the raisin and from the raisin back to the door.
A modified Universal Parkinson’s Disease Rating Scale is used to rate Parkinsonism in the monkeys.
A computerized stereological toolbox software program (stereo investigator) is used to estimate the total number of dopaminergic cells in SNc, on the basis of optical fractionator method.
Subcellular and subsynaptic localization of glutamate receptors in different nuclei of basal ganglia will be analysed using electron microscope.
PD biomarkers like TH, DAT, calbindin and acetylcholine are examined using immunohistochemistry.

Our preliminary PET study shows that MTEP monotherapy significantly protects dopaminergic neurons from the toxic MPTP insult thereby preventing DAT occupancy reduction and the parkinsonian motor symptoms when compared with control monkeys. In addition, MTEP monotherapy showed a modest acute anti-akinetic effect in MPTP monkeys. Further studies arein the process to defined reproducibility and accuracy of the therapeutic approach. I thoroughly enjoy the intellectual and technical challenges of research and the friendly environment in my lab. I believe we may reveal a milestone therapy for PD patients.

Publications

E. Philip Jesudason, B’Joe Baben, Ashok BS, J. Gunasingh Masilamoni, R. Kirubagaran, W. Charles E. Jebaraj & R. Jayakumar. Anti-inflammatory effect of melatonin on Aβ vaccination in mice. Molecular and Cellular Biochemistry 2007, 298, 69-81.

J. Gunasingh Masilamoni, E. Philip Jesudason, Bjoe, Charles E. Jebaraj & R. Jayakumar. The molecular chaperone a-crystallin protects inflammation-induced neurodegeneration. .Biochim Biophys Acta - Molecular Basis of Disease, 2006, 1762, 284 - 291.

J. Gunasingh Masilamoni, Vignesh, R. Kirubagaran, E. Philip Jesudason & R. Jayakumar. The neuroprotective efficacy of a-crystallin against acute inflammation in mice. Brain Research Bulletin 2005, 67 235-241.

J. Gunasingh Masilamoni, E. Philip Jesudason, S. Nirmala Bharathi and R. Jayakumar. The protective effect of a-crystallin against acute inflammation in mice.Biochim Biophys Acta - Molecular Basis of Disease, 2005, 1740, 411-420.

J. Gunasingh Masilamoni, E. Philip Jesudason, K. Samuel Jesudoss, J. Murali, Solomon FD Paul & R. Jayakumar. Role of fibrillar Ab25-35 in the inflammation induced rat model with respect to oxidative vulnerability. Free Radical Research 2005 39 603–612.

E. Philip Jesudason, J. Gunasingh Masilamoni, R. Kirubagaran, G. Dicky John Davis and R. Jayakumar. The protective role of DL-a-lipoic acid in biogenic amines catabolism triggered by Aß amyloid vaccination in mice. Brain Research Bulletin. 2005, 65, 361-367.

E. Philip Jesudason, J. Gunasingh Masilamoni, K. Samuel Jesudoss, & R. Jayakumar The protective role of DL a-Lipoic acid in the oxidative vulnerability triggered by Ab amyloid vaccination in mice. Molecular Cellular Biochemistry. 2005, 270, 29-37.