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Mechanisms of Disease and Treatment in Novel Metabolic Developmental Brain Disorders

Award Number: R01NS121618
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: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Mechanisms of Disease and Treatment in Novel Metabolic Developmental Brain Disorders - PROJECT SUMMARY We have recently identified a novel human neurogenetic disorder caused by loss-of-function mutations in the mitochondrial enzyme glutamate pyruvate transaminase 2 (GPT2). Genetic metabolic diseases, such as GPT2 disease, offer a powerful lens to investigate mechanisms of metabolism in human brain. Also, metabolic diseases may be amenable to treatments via dietary restrictions or supplements. GPT2 disease involves postnatal undergrowth of brain and progressive spastic paraplegia. Based on our extensive preliminary data, we have established potential treatment strategies for GPT2 disease. To guide these interventions in children, we propose to complete needed pre-clinical studies. GPT2 localizes to mitochondria and is upregulated during postnatal brain development. GPT2 catalyzes the reversible addition of an amino group from glutamate to pyruvate, yielding alanine and a-ketoglutarate, a metabolite in the tricarboxylic acid (TCA) cycle. Our preliminary data provide support for disease mechanisms, wherein GPT2 plays a critical role in neuronal growth by regulating neuronal alanine synthesis and anaplerosis. Anaplerosis (filling-up) is the metabolic process whereby TCA cycle intermediates are replenished. Anaplerosis is important during high biosynthetic demand, when TCA cycle intermediates are consumed for synthesis of macromolecules for cell growth, a process known as cataplerosis. Therefore, the central objective of this R01 application is to define the role of GPT2-mediated mechanisms in neuronal development and health, and to study the efficacy of mechanism- based treatments. Aim 1 is focused on in vivo studies of Gpt2-mediated growth of motor neurons. Our Gpt2- null mouse recapitulates key aspects of disease, such as hindlimb motor abnormalities, akin to spastic paraplegia seen in patients. In Aim1 and in Aim 2, we are developing mechanism-based rescue strategies to treat motor defects in vivo through metabolite supplementation in the diets of Gpt2-null animals. Aim 3 will define GPT2-mediated metabolic mechanisms governing neuronal growth and treatments in vitro. These studies are in both primary mouse neurons, as well as in human neurons (from stem cells) in order to translate advances back to the human context. We have a strong and multidisciplinary team permitting a powerful integrated translational approach, bridging patient-oriented studies to experimental models. In summary, research in this proposal will have a sustained impact on both fundamental neuroscience and treatment development. We will evaluate therapeutic strategies that could be rapidly implemented in patients with GPT2 disease, which currently has no known treatment. This progress would pave the way for early intervention, and potentially, prevention of neurologic damage in patients with GPT2 disease. Finally, these studies have broad significance, as we will define basic metabolic mechanisms required for growth and health of long-projecting neurons, including long-projecting motor neurons that are vulnerable in a variety of neurological 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 = $580,106 )
2026	2026	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	3/5/2026	NON-COMPETING CONTINUATION	$58,009
2026	2026	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/10/2025	NON-COMPETING CONTINUATION	$522,097
														Subtotal = $580,106

Issue Date FY: 2025 ( Subtotal = $522,097 )
2025	2025	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/20/2024	NON-COMPETING CONTINUATION	$522,097
														Subtotal = $522,097

Issue Date FY: 2024 ( Subtotal = $562,703 )
2024	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/11/2024	NON-COMPETING CONTINUATION	$40,606
2024	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/21/2023	NON-COMPETING CONTINUATION	$522,097
														Subtotal = $562,703

Issue Date FY: 2023 ( Subtotal = $926,881 )
2023	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	2	3/24/2023	SUPPLEMENT FOR EXPANSION	$314,215
2023	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/25/2022	NON-COMPETING CONTINUATION	$522,097
2023	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	11/28/2022	SUPPLEMENT FOR EXPANSION	$32,560
2023	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	1/30/2023	NON-COMPETING CONTINUATION	$58,009
														Subtotal = $926,881

Issue Date FY: 2022 ( Subtotal = $606,685 )
2022	2022	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/16/2021	NEW	$578,642
2022	2022	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	8/12/2022	SUPPLEMENT FOR EXPANSION	$28,043
														Subtotal = $606,685

Grand Total All Awards = $3,198,472

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Mechanisms of Disease and Treatment in Novel Metabolic Developmental Brain Disorders

Award Number: R01NS121618

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: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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