Thursday, July 3, 2025 7/3/2025

Modeling Parkinson's Disease with Isogenic hiPSC-Derived Dopaminergic Neurons

Award Number: R01NS086890
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2014
PERIOD OF PERFORMANCE END DATE: 06/30/2019

Group Awards By:

View Award Description

Modeling Parkinson's Disease with Isogenic hiPSC-Derived Dopaminergic Neurons - DESCRIPTION (provided by applicant): This R01 grant aims to identify new molecular pathways and treatments to prevent mitochondrial-based injury and dopaminergic (DA) neuronal cell death in Parkinson disease (PD). As tools, we will take advantage of the potential interplay of genes mutated in PD and exposure to environmental risk factors, such as certain pesticides, that might contribute to disease in part as mitochondrial toxins. Although several epidemiological studies have suggested an association of pesticides, particularly the combination of paraquat (PQ) and maneb (MB), to the etiology of PD, evidence for a direct role of their effect on human DA neurons remains poorly studied. One reason for this is the inability to effectively model the disease in human cells, in part due to the nature of PD manifestations (i.e., late onset and slow progression of pathology), and in part due to complications arising from epistatic effects of the patient's genetic background that might influence the outcome after exposure. To overcome these problems, we are using a human iPSC model of PD in which the "control" and mutant cells are genetically identical (isogenic) except for a single pathogenic poin mutation in the a-synuclein locus (A53T). This model gives us an unprecedented opportunity to examine the vulnerability of human A9-type DA neurons after pesticide exposure with regard to genetic background. We mount preliminary data that decreased activity of MEF2, a transcription factor involved in both neurogenesis and neuroprotection, may play a contributory role in PD pathogenesis due to environmental or genetic insult. We find that the pesticides PQ, MB, or rotenone affect mitochondrial function in DA neurons, producing excessive nitric oxide (NO) and reactive oxygen species (ROS). NO/ROS lead to aberrant S-nitrosylation/oxidation of MEF2 (forming SNO-MEF2 and SOH-MEF2). These posttranslational modifications impair MEF2 transcriptional activity. We identify potential downstream cellular events resulting from nitrosylation/oxidation of MEF2, including a decrease in the transcriptional co-activator molecule PGC1a, whose gene is regulated by MEF2 and is a key regulator of mitochondrial function. We will next attempt to rescue hiPSC-derived neurons from PD-related cell death by (a) preventing nitrosylation/oxidation of MEF2 via genetic modification of MEF2, or (b) boosting PGC1a activity. Finally, in our HTS Center, as potential therapeutics we will identify small molecules tht increase MEF2 activity or prevent its oxidation. Thus, these studies will elucidate molecular events linking genetic and environmental risk factors in PD, and we will use this information to develop novel therapeutic targets for drug screening for the treatment of PD in the human context (by using hiPSC-derived DA neurons). As Specific Aims we plan: Aim 1. To characterize environmental risk factor- induced vulnerability in isogenic hiPSC A53T-a-synuclein vs. WT DA neurons (and vs. non-DA neurons). Aim 2. To elucidate pathways for this susceptibility involving SNO-MEF2 of SOH-MEF2. Aim 3. To screen for novel agents that protect from this genetic or environmentally-induced neuronal injury in PD.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2017	SCINTILLON INSTITUTE	6868 NANCY RIDGE DR	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	9/14/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	1/4/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $423,281 )
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	005	7	9/14/2018	NON-COMPETING CONTINUATION	$413,438
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	006	7	9/19/2018	NON-COMPETING CONTINUATION	$9,843
2018	2017	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	6	9/13/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2018	2017	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	6	3/12/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$115,245
2018	2017	SCINTILLON INSTITUTE,THE	6868 NANCY RIDGE DR	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	3/12/2018	NON-COMPETING CONTINUATION	-$115,245
2018	2017	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	2/2/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$177,192
2018	2017	SCINTILLON INSTITUTE,THE	6868 NANCY RIDGE DR	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/1/2018	NON-COMPETING CONTINUATION	-$177,192
														Subtotal = $423,281

Issue Date FY: 2017 ( Subtotal = $413,438 )
2017	2017	SCINTILLON INSTITUTE,THE	6868 NANCY RIDGE DR	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/3/2017	NON-COMPETING CONTINUATION	$413,438
														Subtotal = $413,438

Issue Date FY: 2016 ( Subtotal = $413,438 )
2016	2016	THE SCINTILLON INSTITUTE	6404 NANCY RIDGE DRIVE	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/11/2016	NON-COMPETING CONTINUATION	$413,438
														Subtotal = $413,438

Issue Date FY: 2015 ( Subtotal = $426,563 )
2015	2015	THE SCINTILLON INSTITUTE	6404 NANCY RIDGE DRIVE	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	8/3/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$202,499
2015	2015	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/19/2015	NON-COMPETING CONTINUATION	$426,563
2015	2015	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	7/31/2015	NON-COMPETING CONTINUATION	-$202,499
														Subtotal = $426,563

Issue Date FY: 2014 ( Subtotal = $426,563 )
2014	2014	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/28/2014	NEW	$426,563
														Subtotal = $426,563

Grand Total All Awards = $2,103,283

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Modeling Parkinson's Disease with Isogenic hiPSC-Derived Dopaminergic Neurons

Award Number: R01NS086890

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2014

PERIOD OF PERFORMANCE END DATE: 06/30/2019

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer