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Determining the influence of cellular environments on a-synuclein fibril conformations

Award Number: R21NS136951
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: 03/15/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Determining the influence of cellular environments on a-synuclein fibril conformations - Neurodegeneration in Parkinson's disease (PD) is closely associated with the accumulation of α- synuclein (α-syn) protein aggregates known as Lewy bodies. Understanding the diverse conformations adopted by α-syn in both healthy and diseased states is crucial for developing effective interventions. Recent advances in structural biology have provided valuable insights into the structural diversity of α- syn amyloid fibrils. However, the extent to which these in vitro models represent the conformations amplified in biological settings remains uncertain. This uncertainty hinders our ability to develop tools like PET-tracers, small molecules that bind to amyloid fibrils that can be used to localize and monitor disease progression in vivo. This project aims to bridge this gap by determining if the amyloid conformations that can be propagated in vitro can be propagated inside cells. To do so, we will leverage the sensitivity gains of dynamic nuclear polarization (DNP) nuclear magnetic resonance (NMR) spectroscopy to investigate the conformations of α-syn fibrils amplified inside cells and compare them with in vitro amplified fibrils. By using biosensor cell lines capable of propagating α-syn amyloid conformations, we will examine the structural features of α-syn fibrils in cellular environments. This knowledge will facilitate the optimization of in silico structure-based and chemical screens to identify selective α-syn ligands.


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: 2025 ( Subtotal = $203,203 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/13/2025	NON-COMPETING CONTINUATION	$203,203
														Subtotal = $203,203

Issue Date FY: 2024 ( Subtotal = $244,203 )
2024	2024	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/4/2024	NEW	$244,203
														Subtotal = $244,203

Grand Total All Awards = $447,406

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Determining the influence of cellular environments on a-synuclein fibril conformations

Award Number: R21NS136951

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: 03/15/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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