Loss of dopaminergic neurons is the principal cellular pathology underlying Parkinson's disease (PD). A fundamental but unresolved challenge is how to replenish dopaminergic neurons and restore the neurotransmitter dopamine-regulated neural circuits. Transplantation of dopaminergic neurons into the striatum can reverse behavioral deficits of PD, highlighting the therapeutic value of striatal dopamine. However, the efficacy of transplanted stem cells is limited by the survival and integration of induced neurons, as well as, the potential for tumorigenesis. The long-term goal of this proposal is to define a new regenerative strategy for neuronal induction using patient-specific endogenous glial cells. Our preliminary results show that resident glia can be in vivo reprogrammed into neuroblasts in the adult striatum. These neuroblasts proliferate and generate mature neurons when supplied with neurotrophic factors or the small chemical compounds valproic acid. Most importantly, the newly generated striatal neurons can functionally integrate into local neuronal circuits.
Three aims are proposed in this application to further analyze and optimize the in vivo reprogramming process: 1) to optimize the reprogramming process for the generation of dopaminergic neurons, 2) to functionally characterize these induced dopaminergic neurons in the adult brain, and 3) to examine translatability of induced dopaminergic neurons. The results of this work may lead to an entirely novel treatment paradigm for PD.

Public Health Relevance

Parkinson's disease causes a huge financial and emotional burden to patients and their caregivers in the US. There is currently no effective cure due to permanent loss of neurons. The proposed studies will define a potentially paradigm-shifting therapeutic strategy for PD by converting a patient's own glial cells to dopaminergic neurons in the adult brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS092616-05
Application #
9988510
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Sieber, Beth-Anne
Project Start
2016-08-01
Project End
2021-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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