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Selective galactosylceramidase ablation to study the pathogenesis of Krabbe leukodystrophy

Award Number: R01NS112327
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: 12/13/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2029

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Selective galactosylceramidase ablation to study the pathogenesis of Krabbe leukodystrophy - Krabbe disease (KD), or globoid cell leukodystrophy, is the most fatal form of the demyelinating neurodegenerative lysosomal storage disorders. KD is caused by mutations in the gene for galactosylceramidase (GALC), which results in toxic accumulation of its enzyme targets, psychosine and galactosylceramide. Most cases involve the infantile-onset form, which is typically fatal by 2 years of age. Hematopoietic stem cell transplantation is the only treatment available and partially attenuates the course of KD when delivered before symptoms appear. This highlights our lack of understanding of the basic mechanisms at play and the pathogenic cascade of KD. It is therefore essential to decode cellular responses to the loss of GALC and understand the interplay between the brain cell types driving the demyelination and neurodegeneration. We used a novel conditional Galc knockout (CKO) mouse model in an unbiased approach to evaluate the loss of Galc function in different cell types in the mouse brain in vivo. We found that oligodendrocyte (OL)-specific Galc CKO mice have a KD-like phenotype. Notably, GALC-deficient OLs die by an iron-dependent form of programmed cell death known as ferroptosis. We also conducted Translating Ribosome Affinity Purification (TRAP)-Seq analysis of brain tissue from mice with OL-specific Galc CKO, which revealed a dramatic upregulation of the gene encoding secretory protein lipocalin-2 (LCN2), a target of the proinflammatory transcription factor NF-kB that induces neuroinflammation. Our conditional mouse models also revealed that Galc ablation from both OLs and microglia results in a much more severe KD phenotype. However, the exacerbation occurred in the absence of any additional accumulation of psychosine, indicating an unknown contribution from microglia. Further studies revealed that under conditions of GALC deficiency, microglia upregulate their expression of osteopontin (OPN), a secreted phosphoprotein that recruits additional immune cells and promotes microglial engulfment of debris and damaged cells. Building upon these discoveries, we hypothesize that GALC deficiency in OLs triggers activation of the NF-kB pathway and inflammatory and ferroptotic processes in OLs, which involve the upregulation of LCN2. In addition, GALC-deficient microglia secrete OPN and attract more immune cells to exacerbate neuroinflammation in KD. We propose studies to determine the mechanisms by which (i) GALC-deficient OLs, (ii) GALC-deficient microglia, and (iii) NF-kB activity contribute to KD pathogenesis. By combining a series of in vitro and in vivo experiments, we will study specific molecular mechanisms in which GALC deficiency triggers cell autonomous dysfunctions that progress to manifest as KD. We will decode the cellular interplay between OLs and microglia in the brain that drive the demyelination and neuroinflammation characteristic of this and other neuroinflammatory diseases. These studies will reveal novel pathogenic mechanisms that could translate to important targets for therapeutic interventions.


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 = $411,649 )
2025	2025	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	5/13/2025	COMPETING CONTINUATION	$10,888
2025	2025	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/9/2025	COMPETING CONTINUATION	$411,649
2025	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	5/13/2025	NON-COMPETING CONTINUATION	-$10,888
														Subtotal = $411,649

Issue Date FY: 2023 ( Subtotal = $348,906 )
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	1/30/2023	NON-COMPETING CONTINUATION	$34,890
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/2/2022	NON-COMPETING CONTINUATION	$314,016
														Subtotal = $348,906

Issue Date FY: 2022 ( Subtotal = $348,906 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/23/2021	NON-COMPETING CONTINUATION	$314,015
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	6/23/2022	NON-COMPETING CONTINUATION	$34,891
														Subtotal = $348,906

Issue Date FY: 2021 ( Subtotal = $447,623 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	1/26/2021	NON-COMPETING CONTINUATION	$34,891
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/9/2020	NON-COMPETING CONTINUATION	$314,015
2021	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	12/9/2020	NEW	$98,717
														Subtotal = $447,623

Issue Date FY: 2020 ( Subtotal = $348,906 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/18/2019	NEW	$348,906
														Subtotal = $348,906

Grand Total All Awards = $1,905,990

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Selective galactosylceramidase ablation to study the pathogenesis of Krabbe leukodystrophy

Award Number: R01NS112327

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: 12/13/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2029

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