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Novel methods for small molecule discovery to address alpha-Synuclein induced neuroinflammation

Award Number: R21AG100961
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 05/30/2028

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Novel methods for small molecule discovery to address alpha-Synuclein induced neuroinflammation - ABSTRACT Neurodegenerative diseases such as Parkinson’s and Alzheimer’s are characterized by pathological protein aggregation, chronic inflammation, and selective neuronal loss. Tumor necrosis factor (TNF) signaling has emerged as a central mediator of this inflammatory landscape, yet clinical trials targeting TNF broadly have failed — likely due to their inability to distinguish between protective and neurotoxic pathways. TNF acts through two receptors with divergent functions: TNFR1 promotes inflammation, apoptosis, and necroptosis, while TNFR2 supports neuronal survival and regeneration. Current therapies cannot selectively modulate these distinct pathways, creating a critical gap in precision neuroinflammatory intervention. This proposal pioneers a dual-pronged strategy to restore TNF signaling balance in the context of α-synuclein (aSyn)-induced neurodegeneration. We hypothesize that pathogenic aSyn disrupts TNFR1/TNFR2 equilibrium, favoring cell death over survival. To test this, we will deploy an innovative suite of live-cell biosensors — leveraging our Multiplexed Dark FRET (MDF) technology and newly developed bimolecular fluorescence complementation (BiFC) reporters — to resolve receptor-specific signaling in real time. Aim 1 will generate the first biosensors capable of distinguishing TNFR1 adaptor protein complexes involved in apoptosis (Complex IIa) and necroptosis (Complex IIb) from those mediating survival (Complex I), enabling a high-throughput screen (HTS) for pathway-selective TNFR1 modulators. Aim 2 will establish a first-in-class dual-reporter biosensor for TNFR2 that integrates conformational change sensing (via shadow FRET) with functional RelB translocation (via BiFC), allowing the discovery of small-molecule TNFR2 agonists — a long-standing unmet need in neuroinflammation research. Our biosensor platform distinguishes TNFR1 and TNFR2 target engagement (via MDF) and concomitant TNFR2 activation through RelB translocation. Using these biosensors, we will perform an HTS campaign with the ChemBridge CNSset library, a 50,000-compound library on hand at the BTC that was curated for compounds predicted to have improved blood-brain-barrier permeability. Using 2D and 3D neuron–microglia co-cultures under aSyn pre-formed fibril-induced inflammatory stress, we will evaluate whether selective TNFR1 inhibitors and TNFR2 agonists synergize to restore neuroprotection. This integrated approach offers both mechanistic insights and a therapeutic discovery pipeline, combining advanced biosensor engineering, disease-relevant models, and HTS platforms. By shifting the paradigm from global TNF suppression to receptor- and pathway-specific modulation, this project has the potential to identify next-generation therapeutics for neurodegenerative diseases. Our tools will also serve as a foundation for future R01 studies into TNFR signaling across diverse amyloidogenic pathologies. Ultimately, this work may lead to novel combination therapies that precisely reprogram inflammatory signaling to protect vulnerable neurons without compromising immune surveillance.


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 = $221,279 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Aging Research	000	1	9/10/2026	NEW	$221,279
														Subtotal = $221,279

Grand Total All Awards = $221,279

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Novel methods for small molecule discovery to address alpha-Synuclein induced neuroinflammation

Award Number: R21AG100961

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 05/30/2028

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