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Use of IPSC to define role of astrocytes in specifying risk for onset of cerebral adrenoleukodystrophy

Award Number: R01NS114245
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: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Use of IPSC to define role of astrocytes in specifying risk for onset of cerebral adrenoleukodystrophy - PROJECT SUMMARY/ABSTRACT The mechanism of disease progression from benign to fatal phenotypes in X-linked adrenoleukodystro- phy remains unknown and there is no satisfactory cure for the disease. 60% of male X-ALD patients develop fatal cerebral disease (cALD) while the remaining 40% develop milder adrenomyeloneuropathy (AMN) charac- terized by axonopathy. The primary genetic defect in X-ALD (mutation/deletion in ABCD1 gene) and the bio- chemical defect (accumulation of very long chain fatty acid; C>22:0 in plasma and tissues) cannot predict the onset of AMN or cALD. The long-term goal is to contribute to the development of novel clinically useful, mecha- nism-based prognostic indicators and therapeutic options for X-ALD. The overall objective for this application is to determine differential metabolic energy metabolism underlying phenotype variability (AMN vs cALD) in the human astrocytes of male X-ALD phenotypes. The central hypothesis is that altered metabolic reprogramming underlies the differential phenotype development in AMN and cALD astrocytes. These astrocytes were differen- tiated from induced pluripotent stem cells (iPSCs), which, in turn, were generated by reprogramming of human control, AMN and cALD patient-derived fibroblasts. This hypothesis is supported by untargeted metabolomics pilot data identifying metabolites altered between healthy-control and cALD phenotype postmortem brain and between AMN and cALD astrocytes. Within the cALD brain white matter, unique metabolite changes were rec- orded between distant normal looking areas and areas adjacent to the plaque suggesting an association with disease progression. OXPHOS and glycolysis were found to be decreased (low metabolic state) in human cALD astrocytes. This low metabolic state suggests a role for novel alternative source(s) of fuel driving the progression to cALD phenotype in astrocytes. The rationale for the proposed research is that a mechanistic modelling of aberrant energy metabolism in AMN and cALD astrocytes will provide a basis for predicting disease progression and new opportunities for identification of targets for novel therapeutic drug design. The central hypothesis will be tested by pursuing two specific aims: 1) Determine the role of metabolic reprogramming in newly “forged” AMN and cALD astrocytes; and 2) Determine the contribution of mitochondrial dysfunction in metabolic repro- gramming in AMN and cALD astrocytes. The approach will take advantage of control, AMN and cALD astrocytes recently generated from iPSCs in the laboratory. This proposal is innovative because it departs from the status quo by identifying for the first time, metabolic pathways differentially altered in human AMN and cALD astrocytes. The proposed research is significant because the cellular mechanism(s) that lead to less severe AMN or fatal cALD phenotype in response to same ABCD1 mutation remain unknown even four decades after the identifica- tion of gene defect in X-ALD. Successful completion of the proposed research is expected to provide a necessary conceptual framework for the subsequent development of clinically effective strategies for predicting disease progression and improving current limited treatment options.


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: 2024 ( Subtotal = $343,065 )
2024	2024	HENRY FORD HEALTH SYSTEM	1 FORD PL	DETROIT	MI	48202	WAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/7/2024	NON-COMPETING CONTINUATION	$343,065
														Subtotal = $343,065

Issue Date FY: 2023 ( Subtotal = $353,675 )
2023	2023	HENRY FORD HEALTH SYSTEM	1 FORD PL	DETROIT	MI	48202	WAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/30/2023	NON-COMPETING CONTINUATION	$353,675
														Subtotal = $353,675

Issue Date FY: 2022 ( Subtotal = $445,921 )
2022	2022	HENRY FORD HEALTH SYSTEM	1 FORD PL	DETROIT	MI	48202	WAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/14/2022	NON-COMPETING CONTINUATION	$353,675
2022	2021	HENRY FORD HEALTH SYSTEM	1 FORD PL	DETROIT	MI	48202	WAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	10/8/2021	NEW	$92,060
2022	2021	HENRY FORD HEALTH SYSTEM	1 FORD PL	DETROIT	MI	48202	WAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	9/23/2022	NEW	$186
														Subtotal = $445,921

Issue Date FY: 2021 ( Subtotal = $353,675 )
2021	2021	HENRY FORD HEALTH SYSTEM	1 FORD PLACE	DETROIT	MI	48202	WAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/21/2021	NEW	$353,675
														Subtotal = $353,675

Grand Total All Awards = $1,496,336

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Use of IPSC to define role of astrocytes in specifying risk for onset of cerebral adrenoleukodystrophy

Award Number: R01NS114245

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: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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