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Region-Specific Vulnerability of the Lewy Body Dementia's Brain

Award Number: R01NS123456
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: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Region-Specific Vulnerability of the Lewy Body Dementia's Brain - REGION-SPECIFIC VULNERABILITY OF THE LEWY BODY DEMENTIA’S BRAIN PROJECT SUMMARY Lewy Body Dementia (LBD) is a progressive neurodegenerative disorder characterized by aggregation of the α- synuclein (α-syn) into intracellular inclusions called Lewy bodies (LB) and Lewy neurites (LN). This form of dementia belongs to a class of neurodegenerative diseases termed “synucleinopathies.” LBD is the most common neurodegenerative dementia after Alzheimer’s disease. In LBD, dementia usually proceeds to the onset of parkinsonian motor symptoms with neurobehavioral symptoms that may be accompanied by both cognitive and motoric dysfunction. While various misfolded oligomers, primarily constituted of α-syn, are associated with the development of dementia along with neuronal loss, there is still insufficient understanding of the pathogenesis process. Especially, particular brain areas such as the limbic system and neocortex are more vulnerable than other regions. Researchers have considered that the answer to this question will provide a key clue to understanding the pathogenesis mechanism. Inter-cellular crosstalk of neurons, microglia, and astrocytes results in complex physiologies and cellular behaviors, potentially leading to neuronal loss. Moreover, there is brain region-specific heterogeneity in cellular populations of neurons, microglia, and astrocytes that can contribute to the region-specific vulnerability of the LBD brain. Therefore, information on cell-type-specific and single-cell- specific proteome and transcriptome over multiple brain regions is indispensable for understanding this complex mechanism. To study this complex mechanism, the selection of the right aminal model that best recapitulates the human LBD pathogenesis process is crucial. The mouse model that recapitulates the Braak hypothesis would serve as the best animal model and we recently have generated this mouse model (gut-brain α-syn model) successfully by injecting α-syn to the gut. To study the regional vulnerability of LBD using the mouse model, we propose 1) to study region- and cell-type-specific proteome of the brain of the gut-brain α-syn model using BONCAT and xMD, 2) to study region- and single-cell-specific transcriptome of the brain of the gut-brain α-syn model using HiF-snRNAseq, 3) to perform integrative bioinformatic analysis and validate the affected pathways found in the mouse models using the human brain. Cell-type-specific proteome analysis and single-cell transcriptome analyses over multiple brain regions of the gut-brain α-syn model proposed in this application will enable us to identify region- and cell-type-specific signaling pathways that are involved in region-specific vulnerabilities to pathological α-syn. This novel information will contribute to a better understanding of LBD pathogenesis. Furthermore, these approaches can be expanded to studying pathogenesis mechanisms of other neurodegenerative diseases.


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 = $0 )
2026	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/4/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $737,778 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/4/2025	NON-COMPETING CONTINUATION	$737,778
														Subtotal = $737,778

Issue Date FY: 2024 ( Subtotal = $737,778 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/27/2024	NON-COMPETING CONTINUATION	$737,778
														Subtotal = $737,778

Issue Date FY: 2023 ( Subtotal = $753,716 )
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/8/2023	NON-COMPETING CONTINUATION	$753,716
														Subtotal = $753,716

Issue Date FY: 2022 ( Subtotal = $664,314 )
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/22/2022	NON-COMPETING CONTINUATION	$664,314
														Subtotal = $664,314

Issue Date FY: 2021 ( Subtotal = $664,314 )
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/22/2021	NEW	$664,314
														Subtotal = $664,314

Grand Total All Awards = $3,557,900

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Region-Specific Vulnerability of the Lewy Body Dementia's Brain

Award Number: R01NS123456

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: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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