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Sigma-1 Receptor as a modulator of Astrocyte pro-inflammatory activities in Parkinson's Disease

Award Number: F30AG087521
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/02/2024
PERIOD OF PERFORMANCE END DATE: 12/01/2027

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Sigma-1 Receptor as a modulator of Astrocyte pro-inflammatory activities in Parkinson's Disease - PROJECT SUMMARY The objective of this proposal is to characterize a regulatory signaling axis which promotes astrocyte-driven CNS pathology in Parkinson’s Disease (PD) and to provide the necessary training for me to become a successful physician-scientist. PD is characterized by progressive motor deficits, neurodegeneration, and neuroinflammation. α-synuclein (αSyn) aggregates into fibrils in PD and injection of pre-formed αSyn fibrils (PFFs) into the mouse striatum recapitulates hallmarks of PD pathology. Astrocytes regulate central nervous system (CNS) inflammation in neurologic diseases including PD and Multiple Sclerosis (MS) via interactions with other cells including microglia. PD-associated stimuli such as αSyn further trigger astrocyte pro-inflammatory functions. Critically, blockade of astrocyte inflammatory activities in PD and MS models ameliorates disease. However, the pathways that modulate astrocyte activity in PD are poorly characterized. Thus, a deeper mechanistic understanding of these regulatory pathways is likely to identify mechanisms of disease pathogenesis and potential therapeutic targets for PD. The Quintana lab previously showed that the sigma-1 receptor (SigmaR1) boosts astrocyte pro-inflammatory responses through the activation of the IRE-1α-XBP1 signaling in a MS mouse model. Furthermore, astrocyte- specific SigmaR1 knockout reduces astrocyte and microglia pro-inflammatory responses, suggesting that that SigmaR1 signaling in astrocytes boosts microglial pro-inflammatory functions. I have shown in vitro that astrocytes treated with αSyn PFFs and cytokines display upregulation of XBP1 and the pro-inflammatory molecule IL-1β. In vivo, I have shown that SigmaR1 inactivation prevent the development of motor deficits in response to PFF injection. Thus, my data suggests that αSyn incites XBP1 and pro-inflammatory signaling and SigmaR1 inhibition can prevent hallmarks associated with PD. In this proposal, I will test the hypothesis that SigmaR1 inhibition will limit astrocyte pro-inflammatory functions and CNS pathology in PD. In Specific Aim 1, I will evaluate the role of SigmaR1 on astrocyte and astrocyte-microglia pro-inflammatory responses induced by PFFs and cytokines. In Specific Aim 2, I will evaluate the effect of genetic and pharmacologic SigmaR1 blockade on CNS pathology and inflammation in the pre-clinical mouse model of PD induced by injection of PFFs. Completion of these aims will characterize astrocyte responses to αSyn, their interactions with microglia, and the regulation of their disease promoting activities in PD. Furthermore, this proposal will integrate the clinical and research training necessary for me to become an independent physician-scientist.


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 = $55,114 )
2026	2026	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Aging Research	001	2	3/25/2026	NON-COMPETING CONTINUATION	$576
2026	2026	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Aging Research	000	2	1/15/2026	NON-COMPETING CONTINUATION	$54,538
														Subtotal = $55,114

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Aging Research	000	1	11/21/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $53,974 )
2024	2024	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Aging Research	000	1	8/15/2024	NEW	$53,974
2024	2024	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Aging Research	001	1	8/15/2024	NEW	$0
														Subtotal = $53,974

Grand Total All Awards = $109,088

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Sigma-1 Receptor as a modulator of Astrocyte pro-inflammatory activities in Parkinson's Disease

Award Number: F30AG087521

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/02/2024

PERIOD OF PERFORMANCE END DATE: 12/01/2027

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