Development and testing of disease-modifying therapies for Parkinson's disease (PD) is limited, in part, by lack of predictive animal models. We propose to develop and characterize a better, more predictive model, with (i) a more realistic time course, (ii) appropriate pathological and behavioral endpoints and (iii) opportunities to intervene therapeutically at clinically relevant points in the disease course (e.g., after development of symptoms). We believe the new model will set a higher and more realistic hurdle for experimental, disease-modifying therapies, and in so doing, will have more predictive value for clinical development. In brief, wildtype rats are treated with rotenone for 5 days (instead of the typical 14-21 days), during which they displayed mild parkinsonian behavior. After cessation of the rotenone, the rats recover and are behaviorally normal. After a latency of 9 ? 10 weeks, all of the rats begin to exhibit mild parkinsonian signs that have continued to worsen progressively over succeeding weeks and months. Preliminary pathological assessment reveals that nigral dopamine neurons progressively accumulate abnormal endogenous ?-synuclein long before behavioral signs appear and this is associated with increasing microglial activation. We now propose to further characterize this model and to test a therapeutic intervention with the following aims: (1) To characterize selected `clinical' or behavioral aspects of this model over the course of 1 year. Behaviors include the Postural Instability Test (PIT), rearing, righting behavior and gait. (2) To characterize over time the pathology in this model, including nigrostriatal cell and terminal loss, ?-synuclein pathology and markers of inflammation. (3) To test a therapeutic intervention (?-synuclein knockdown) after the onset of symptoms ? a situation closely analogous to clinical medicine, where a diagnosis of PD currently depends on the presence of symptoms.

Public Health Relevance

We propose to characterize and further develop a novel progressive model of Parkinson's disease. We believe this model has more construct and face validity than other PD models and will have better predictive value for development of disease-modifying therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21ES027470-02
Application #
9419921
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Hollander, Jonathan
Project Start
2017-02-01
Project End
2019-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213