Parkinson's disease (PD) is the second most common and debilitating age-associated human neurodegenerative disorder. Clinically, PD is characterized by tremor, slowness of movement, stiffness, and postural instability. Pathologically, it is indicated by activation of glial cells and progressive degeneration of the nigrostriatal dopaminergic neurons associated with the presence of intracytoplasmic inclusions (Lewy bodies). This application addresses an important aspect of PD. Although the rate of disease progression varies from patient to patient, PD is a progressive neurodegenerative disorder. However, the mechanism behind disease progression is poorly understood. We hypothesize that RANTES and eotaxin could hold the key for driving disease progression and that targeting these two chemokines may be an important strategy to control T cell infiltration and hence the disease progression in PD. Here this hypothesis will be tested from several experiments on mice, monkeys and humans. It is known that nigrostriatal pathology does not persist in acute MPTP mouse model.
Under Specific aim I, we will investigate if supplementation of RANTES and eotaxin induces persistent and progressive disease in acute MPTP-intoxicated mice.
Specific aim II has been planned to determine whether PD patients have higher levels of RANTES and eotaxin by monitoring the level of these two chemokines in serum of PD patients and age-matched controls. Finally, we have devoted the Specific aim III to delineate if blocking the functions of RANTES and eotaxin by maraviroc, an inhibitor of CCR5 and a FDA- approved drug, halt the disease progression in hemiparkinsonian monkeys. A positive outcome of this study will establish RANTES and eotaxin as targets for PD, translate CCR5-based treatment (maraviroc) to PD clinic, uncover the clue for the progression of PD, and find a drug to stop the progression of PD.

Public Health Relevance

Parkinson's disease (PD) is a progressive neurodegenerative disorder. However, the mechanism behind disease progression is poorly understood. Here we will test the hypothesis that RANTES and eotaxin are key chemokines for driving disease progression and that targeting these two chemokines may be an important strategy to control the disease progression in PD. A positive outcome of this study will establish RANTES and eotaxin as targets for PD, translate CCR5-based treatment (maraviroc) to PD clinic, uncover the clue for the progression of PD, and find a drug to stop the progression of PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS083054-01A1
Application #
8604071
Study Section
Special Emphasis Panel (ZRG1-BDCN-W (02))
Program Officer
Sieber, Beth-Anne
Project Start
2013-09-30
Project End
2018-07-31
Budget Start
2013-09-30
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$334,688
Indirect Cost
$115,938
Name
Rush University Medical Center
Department
Neurosciences
Type
Schools of Medicine
DUNS #
068610245
City
Chicago
State
IL
Country
United States
Zip Code
60612
Roy, Avik; Rangasamy, Suresh Babu; Kundu, Madhuchhanda et al. (2016) BPOZ-2 Gene Delivery Ameliorates Alpha-Synucleinopathy in A53T Transgenic Mouse Model of Parkinson's Disease. Sci Rep 6:22067
Ghosh, Arunava; Pahan, Kalipada (2016) PPARα in lysosomal biogenesis: A perspective. Pharmacol Res 103:144-8
Roy, Avik; Kundu, Madhuchhanda; Jana, Malabendu et al. (2016) Identification and characterization of PPARα ligands in the hippocampus. Nat Chem Biol 12:1075-1083
Chandra, Goutam; Rangasamy, Suresh B; Roy, Avik et al. (2016) Neutralization of RANTES and Eotaxin Prevents the Loss of Dopaminergic Neurons in a Mouse Model of Parkinson Disease. J Biol Chem 291:15267-81
Bera, Swapna; Kar, Rajiv K; Mondal, Susanta et al. (2016) Structural Elucidation of the Cell-Penetrating Penetratin Peptide in Model Membranes at the Atomic Level: Probing Hydrophobic Interactions in the Blood-Brain Barrier. Biochemistry 55:4982-96
Roy, Avik; Pahan, Kalipada (2015) PPARα signaling in the hippocampus: crosstalk between fat and memory. J Neuroimmune Pharmacol 10:30-4
Corbett, Grant T; Gonzalez, Frank J; Pahan, Kalipada (2015) Activation of peroxisome proliferator-activated receptor α stimulates ADAM10-mediated proteolysis of APP. Proc Natl Acad Sci U S A 112:8445-50
Rangasamy, Suresh B; Corbett, Grant T; Roy, Avik et al. (2015) Intranasal Delivery of NEMO-Binding Domain Peptide Prevents Memory Loss in a Mouse Model of Alzheimer's Disease. J Alzheimers Dis 47:385-402
Roy, A; Mondal, S; Kordower, J H et al. (2015) Attenuation of microglial RANTES by NEMO-binding domain peptide inhibits the infiltration of CD8(+) T cells in the nigra of hemiparkinsonian monkey. Neuroscience 302:36-46
Roy, Avik; Jana, Malabendu; Kundu, Madhuchhanda et al. (2015) HMG-CoA Reductase Inhibitors Bind to PPARα to Upregulate Neurotrophin Expression in the Brain and Improve Memory in Mice. Cell Metab 22:253-65

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