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Crosstalk Between Nurr1 and Risk Factors of Parkinson's Disease and its Regulation by Nurr1's Ligands

Award Number: R01NS127391
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: 05/01/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Crosstalk Between Nurr1 and Risk Factors of Parkinson's Disease and its Regulation by Nurr1's Ligands - Abstract: Selective degeneration of midbrain dopaminergic (mDA) neurons in the substantia nigra and abnormal accumulation and aggregation of α-synuclein in Lewy bodies are hallmark pathological features of Parkinson’s disease (PD). Currently, available treatments are symptomatic and there is no treatment that can halt or slow down the disease progression. Based on extensive studies on transcriptional regulation of mDA neurons from this and other laboratories, the orphan nuclear receptor Nurr1 (also known as NR4A2) has emerged as a master regulator of mDA neurons and a promising target for therapeutic development in PD. Although Nurr1 has been considered a ligand-independent, constitutively active transcription factor, we identified both synthetic (amodiaquine, chloroquine, and glafenine) and endogenous ligands (prostaglandin E1 (PGE1) and PGA1), which directly interact with the ligand binding domain (LBD) of Nurr1 and activate its transcription function with distinct mechanisms. Furthermore, our preliminary data showed that Nurr1 expression is significantly compromised by both prolonged exposure to neurotoxin and overexpression of α-synuclein. Based on these results, we hypothesize that Nurr1 is an “adopted” nuclear receptor whose transcriptional function is significantly modulated by both synthetic and native ligands and that there is functional crosstalk between Nurr1 and PD risk factors. To address these hypotheses, we propose to investigate the following questions. First, we will address whether there exist additional endogenous ligands in the brain and will investigate the underlying molecular mechanisms how these novel ligands regulate Nurr1’s transcriptional function by identifying its coregulators and delineating their structure-activity relationships. Second, we will investigate whether there is crosstalk between Nurr1 and PD risk factors such as α-synuclein and how Nurr1’s ligands regulate this crosstalk. Third, using in vivo models of PD, we will systematically investigate whether Nurr1’s optimal synthetic and/or endogenous ligands can provide mechanism-based neuroprotection for eventual application as novel therapeutics for PD. If successful, these studies will advance our understanding of Nurr1’s function and regulation by its ligands in health and disease, and address whether Nurr1 can be a “druggable” target for 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: 2026 ( Subtotal = $432,440 )
2026	2026	THE MCLEAN HOSPITAL CORPORATION	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/1/2026	NON-COMPETING CONTINUATION	$432,440
														Subtotal = $432,440

Issue Date FY: 2025 ( Subtotal = $432,440 )
2025	2025	THE MCLEAN HOSPITAL CORPORATION	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/25/2025	NON-COMPETING CONTINUATION	$432,440
														Subtotal = $432,440

Issue Date FY: 2024 ( Subtotal = $419,469 )
2024	2024	THE MCLEAN HOSPITAL CORPORATION	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/7/2024	NON-COMPETING CONTINUATION	$419,469
														Subtotal = $419,469

Issue Date FY: 2023 ( Subtotal = $479,123 )
2023	2023	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/17/2023	NEW	$479,123
														Subtotal = $479,123

Grand Total All Awards = $1,763,472

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Crosstalk Between Nurr1 and Risk Factors of Parkinson's Disease and its Regulation by Nurr1's Ligands

Award Number: R01NS127391

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: 05/01/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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