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Assessing the Contribution of Cortical Hyperactivity to ALS Phenotypes in a Human-Derived Motor System

Award Number: F31NS135955
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Assessing the Contribution of Cortical Hyperactivity to ALS Phenotypes in a Human-Derived Motor System - PROJECT SUMMARY/ABSTRACT Amyotrophic Lateral Sclerosis (ALS) is a lethal neurodegenerative disease characterized by motor neuron degeneration. While the presentation of ALS involves progressive loss of motor function, the mechanistic cause(s) of ALS are unknown. Patients diagnosed with ALS may have one of several identified genetic mutations which predispose them to ALS, or they may present no known genetic variation; they may have a familial history of disease, or they may be the first known case in their family. This heterogeneity has complicated our ability to model ALS, obscuring the identification of causative mechanisms in this disease. Current model systems of ALS are limited to exploring the resulting pathologies in animals or cell lines with a single mutation, which ultimately is not representative of the ALS patient population. Furthermore, findings in these models have failed to translate in the vast majority of clinical trials. Remarkably, cortical hyperexcitability is an early biomarker of ALS regardless of genetic background, and it precedes motor symptoms and diagnosis. Despite the well-documented evidence of this early, common phenotype, no study has demonstrated the consequences of this phenomena in human tissue. Cortical projection neurons are in close contact with interneurons, motor neurons, and astrocytes at the cortico-spinal synapse, and we hypothesize that cortical hyperexcitability can induce ALS phenotypes in these populations. Completion of this proposal will determine the effect of cortical hyperexcitability on these three cell-types key to ALS pathology. This proposal will leverage the growing field of human organoid systems to address the lack of access to functional human tissue. Cortico-motor assembloids are formed by assembling human stem cell-derived cortical, spinal, and muscle spheroids. Neurons from the cortical spheroid project to the spinal spheroid. Motor neurons from the spinal spheroid functionally project to the muscle spheroid and induce its contraction. By chronically stimulating the cortical spheroid using optogenetic paradigms informed by findings in the ALS literature, I will recapitulate an early phenotype of ALS within a model derived from healthy control cells, detangling the potential contribution of genetic background. In Aim 1, I will interrogate changes in interneuron and motor neuron populations in the spinal spheroid after stimulation. Drawing from findings in ALS patients and models, we will measure changes in the proportion of inhibitory synapses in the spinal spheroid, as well as changes in muscle innervation and contraction. In Aim 2, I will isolate astrocytes from the spinal spheroid after stimulation and evaluate their ability to transport glutamate, an essential astrocyte function which is compromised in ALS patient-derived tissue. Completion of these aims will begin to elucidate the relationship between disparate ALS pathologies, paving the way towards the identification of disease-modifying targets which are sensitive to the early cortical hyperexcitability phenotype.


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 = $49,538 )
2026	2026	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/25/2026	NON-COMPETING CONTINUATION	$49,538
														Subtotal = $49,538

Issue Date FY: 2025 ( Subtotal = $49,538 )
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	9/8/2025	NON-COMPETING CONTINUATION	$564
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/2/2025	NON-COMPETING CONTINUATION	$48,974
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	4/9/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $49,538

Issue Date FY: 2024 ( Subtotal = $48,974 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/12/2023	NEW	$47,694
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	5/14/2024	NEW	$1,280
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	12/12/2023	NEW	$0
														Subtotal = $48,974

Grand Total All Awards = $148,050

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Assessing the Contribution of Cortical Hyperactivity to ALS Phenotypes in a Human-Derived Motor System

Award Number: F31NS135955

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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