Stephen Traynelis, PhD – Emory University
“The Role of Adenosine A2A Receptors in Microglial Activation”
Dr. Traynelis is a distinguished senior investigator who has recently become interested in the mechanisms contributing to the progressive loss of the striatal dopamine innervation in PD. Dopamine D2 and adenosine A2A receptors are colocalized in striatal neurons. This has led to the suggestion that A2A antagonists may functionally overcome the loss of signaling through the D2 receptor that is present in PD, and a number of A2A compounds have been generated and tested in PD patients. The results suggest mild symptomatic benefit, although the FDA recently denied approval to one such compound, asking for additional data. Traynelis, a senior investigator not previously involved in PD research, has found that A2A receptors are critically involved in microglial activation, and using a novel and inventive experimental approach provided data that A2A mediate repulsion of microglia. Activated microglia are markedly increased in PD and have been suggested to be involved in the progressive loss of dopamine nigrostriatal neurons. This application will examine A2A-mediated microglial activation, and the results may suggest that A2A antagonists should be considered in light of disease progression, not just symptomatic benefit. Eugene Mosharov, PhD – Columbia University
“Regulation of Cytosolic Dopamine by Ca2+ in Ventral Midbrain Neurons”
Dr. Mosharov is a young scientist who has developed an ingenious method for monitoring the concentration of dopamine inside of neurons. There have been arguments that because dopamine is subject to oxidation, which can result in compounds that promote oxidative stress on dopamine neurons, that levodopa treatment may actually accelerate loss of dopamine neurons. This speculation ignores the fact that dopamine in the cytosol of the cell is very rapidly accumulated into vesicles, in which the conditions are favorable for stabilization of dopamine and prevent its oxidation. Recent data indicate that intracellular calcium may be crucial to the survival of dopamine neurons, particularly substantia nigra dopamine neurons. Mosharov has proposed to determine if intracellular calcium levels regulate intracellular (cytosolic) levels of dopamine, both under normal conditions and when levodopa is added. This research will accomplish two goals: 1) it should conclusively show if cytosolic dopamine under levodopa-treated conditions is increased and toxic to the cell, and 2) it may reveal why neurons of the substantia nigra are particularly vulnerable in PD.
Esti Yeger-Lotem, PhD –Whitehead Institute for Biomedical Research, MIT
“Revealing Cellular Pathways Leading to Parkinson's Disease Using a Computational Systems Biology Approach” Dr. Yeger-Lotem is a postdoctoral fellow in Susan Lindquist’s group at MIT. He received his training in computational molecular biology and bioinformatics at the Technion in Israel. He has expertise in profiling gene changes in various systems, and has found that changes intranscription (mRNA) and DNA probe distinct but partial aspects of the process in human and yeast models of disease. He is applying a novel computational approach he has developed (called ResponseNet) that bridges the gap between the transcriptional and genetic read outs to a yeast model of parkinsonism. He will then expand to human idiopathic PD. Current approaches to unbiased profiling of changes in genes or their transcripts typically identify a large number of genes whose expression is altered but places these data into a unified framework that can be efficiently exploited to uncover hitherto unknown interactions between genes and thus new targets for drug development. Yvonne Schmitz, PhD – Columbia University
“Glycine Uptake Inhibitors as Potential Promoters of Axonal Growth and Dopamine Release in Parkinson's Disease” Dr. Schmitz is a junior faculty member in the Department of Neurology at Columbia. Recognizing that axonal sprouting is one of the compensatory responses made by those surviving dopamine neurons in the substantia nigra in PD, she has proposed to use a novel approach she developed to screen for dopaminergic axonal sprouting and its functional consequences, and to examine the effects of a drug that blocks reuptake of glycine on axonal spouting. Supported by compelling preliminary data, Dr. Schmitz proposes to use glycine transporter inhibitors to determine if they enhance axonal sprouting of dopamine neurons in vitro and in vivo. These glycine transporter inhibitors have been studied clinically in schizophrenia, where they did not prove effective for remediating cognitive deficits, but did prove to be very well tolerated. The proposed studies are quite novel and if positive results are obtained could be relatively quickly studied in patients.
Christophe Lo Bianco, PhD – Wallenburg Neuroscience Center at Lund University
“Understanding the Role of Ageing and Mitochondrial DNA Mutations in Parkinson's Disease” Dr. Lo Bianco is a postdoctoral fellow in Anders Bjorklund's lab in Lund. He received his training in Neuroscience with an emphasis in gene therapy approaches to treatment of degenerative disorders in Switzerland, and moved in 2005 to Sweden to extend his work in collaboration with Dr. Bjorklund’s group. They will use a recently developed transgenic mouse that has somatic mitochondrial DNA (mtDNA) mutations causing a progressive respiratory chain deficiency and premature ageing. Dr. Lo Bianco proposes to use a mutant mouse line with a premature human-like ageing phenotype and progressive mitochondrial impairment for investigating whether ageing is a promoting factor of the synuclein–induced neurodegeneration, in order to develop a relevant and progressive model of PD. The lack of a slowly progressive model makes it difficult to decide the best strategies to test in clinical trials, which are extremely expensive. This project, if successful, should help provide a rationale selection of the most likely treatments to succeed in clinical trials of treatments aimed at slowing or halting the progression of PD.
Andrea Giuffrida, PhD – University of Texas Health Science Center
“PPAR Receptors: A New Target for the Treatment of Levodopa-Induced Dyskinesias” Dr. Giuffrida is an Assistant Professor in Pharmacology. He has been a major contributor to elucidating the role of endocannabinoids (lipids related to the active components of cannabis) in basal ganglia function. During these studies he observed that endocannabinoids blocked dyskinesias if given together with capsazepine, but found unexpectedly that this anti-dyskinetic effect was not due to changes in endocannabinoid systems, but instead to a group of receptors (peroxisome proliferators-activated receptors (PPAR) that regulate lipid metabolism, neuronal excitability and synaptic plasticity, with the endocannabinoids activating two types of PPARs. He has proposed a series of studies comparing the effects of certain cannabinoid-like drugs and selective PPAR agonists, together and alone, on levodopa-induced dyskinesias. Because studies of drugs that selectively target different types of PPARs are ongoing for several diseases, if these studies characterize the exact mechanism of PPAR agonists in reducing dyskinesias, it should be possible to move relatively quickly to try these agents in PD patients. Claudio Hetz , PhD – University of Chile
“Defining the Contribution of Endoplasmic Reticulum (ER) Stress in Parkinson's Disease” Dr. Hetz is an Assistant Professor at the University of Chile, and an adjunct Assistant Professor in the School of Public Health at Harvard. After his doctoral training in Chile he did postdoctoral fellowships at the Dana-Farber Cancer Research Institute of Harvard and at the Harvard School of Public Health before returning in 2006 to Chile. He has been a significant contributor to our understanding of mechanisms of cell death, ranging from chaperone-mediate autophagy to apoptosis. He has proposed studies aimed at understanding responses to intracellular stress (called the Unfolded Protein Response, or UPR) on cell death, both alone and as a factor in synuclein-induced cell death in an elegant series of cell biological studies. These studies will illuminate the coordinated activity of the many steps in the UPR and if successful will illuminate new targets for therapeutic intervention in PD aimed at slowing disease progression.
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