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Understanding the Role of Endoplasmic Reticulum-Exit Site Upregulation in Neuroprotection Against Parkinson’s Disease

Award Number: F30NS141487
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/01/2025
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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Understanding the Role of Endoplasmic Reticulum-Exit Site Upregulation in Neuroprotection Against Parkinson’s Disease - Project Summary Parkinson’s disease (PD) is the second-most common neurodegenerative disorder globally and is increasing in prevalence in the United States. At a cellular level, this devastating disease is characterized by a progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc), resulting in a wide range of motor and non-motor symptoms. Neuroprotective therapies for PD are currently lacking, and most treatment modalities are designed to reduce motor symptoms rather than inhibit neurodegeneration. With advancements in PD diagnostics offering the promise of earlier detection, there is an urgent need for neuroprotective strategies capable of arresting DA neuron loss at early stages. Endoplasmic reticulum (ER) stress is a convergent mechanism in DA neuron degeneration, making it a key therapeutic target for neuroprotection against PD. Nicotine and the smoking cessation drug cytisine attenuate ER stress at low doses by acting as a pharmacological chaperone for neuronal nicotinic acetylcholine receptors and consequently increasing the formation of Sec24D-containing endoplasmic reticulum-exit sites (Sec24D-ERES). Furthermore, preliminary data show that cytisine upregulates Sec24D-ERES in a female 6- hydroxydopamine (6-OHDA) mouse model of parkinsonism, which is associated with neuroprotection in female mice only. Astrocytes in the SNc, which also contain Sec24D-ERES, ensheathe DA neurons and undergo process retraction as well as reduced GFAP expression after treatment with low-dose cytisine. Therefore, the overarching hypothesis of this proposal is that cytisine-induced increases in Sec24D-ERES formation in both SNc DA neurons and astrocytes is necessary for neuroprotection in a 6-OHDA mouse model of parkinsonism. This hypothesis will be tested by knocking down expression of Sec24D in a cell type-specific manner to address the following aims: Aim 1: To determine the extent to which Sec24D-ERES upregulation in SNc DA neurons is critical for cytisine- mediated neuroprotection in a 6-OHDA mouse model of parkinsonism. Aim 2: To determine the extent to which Sec24D-ERES upregulation in SNc astrocytes is critical for cytisine- mediated neuroprotection in a 6-OHDA mouse model of parkinsonism. These studies are expected to lay the foundation for developing translational treatment strategies for PD focused on Sec24D-ERES upregulation in DA neurons and astrocytes. This aligns with the mission of the National Institute for Neurological Disorders and Stroke, which is to reduce disease burden for all people by conducting basic and translational research. Completion of this training will enable the development of skills to investigate cellular mechanisms of neuroprotective drugs, which is vitally important to a career goal of becoming a physician-scientist investigating translational therapies for neurodegenerative disorders.


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 = $38,361 )
2026	2026	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/29/2026	NON-COMPETING CONTINUATION	$38,361
														Subtotal = $38,361

Issue Date FY: 2025 ( Subtotal = $38,132 )
2025	2025	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	9/9/2025	NEW	$564
2025	2025	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	1/3/2025	NEW	$0
2025	2025	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/3/2025	NEW	$37,568
														Subtotal = $38,132

Grand Total All Awards = $76,493

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Understanding the Role of Endoplasmic Reticulum-Exit Site Upregulation in Neuroprotection Against Parkinson’s Disease

Award Number: F30NS141487

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/01/2025

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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