Thursday, November 20, 2025 11/20/2025

The Genetics of the Neuromuscular Junction: Mechanisms and Disease Models

Award Number: R37NS054154
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: 08/01/2025
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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The Genetics of the Neuromuscular Junction: Mechanisms and Disease Models - PROJECT SUMMARY Re-training supplement request for R37NS054154 under NOT-OD-23-170 The overall goal of R37NS054154 is to understand the molecular mechanisms through which dominant mutations in tRNA synthetase genes cause Charcot-Marie-Tooth type 2D and related inherited peripheral neuropathies. Towards this, we will 1) examine the biochemical interactions of the mutant synthetases and their cognate tRNAs, 2) explore why only alpha motor neurons and a subset of sensory neurons are affected by these mutations, and 3) test the therapeutic potential of inhibiting the integrated stress response, which is activated by these mutations. Much of this work has been done in mouse models of these diseases, but to extend these studies into a human system, we have engineered GARS/CMT2D mutations into a healthy control iPSC line, KOLF2, which we can differentiate into motor neurons in vitro. We have encountered two challenges with this experimental system. First, the motor neurons are still immature in culture. We have assessed this in part by testing the extent to which they turn on eEF1A2 and turn off eEF1A1. This developmental switch occurs in the first few weeks of life in mice, correlating with the onset of neuropathy in our Gars mice, and we believe it to be central to the cell-type specificity of tRNA synthetase mutations, since eEF1As directly interact with tRNA synthetases and charged tRNAs. Thus, we need to develop sophisticated hiPSC co-culture systems to generate more mature motor neurons that switch more completely to eEF1A2. Second, inhibiting the integrated stress response in our mouse models is highly efficacious, but the rapid response to inhibition and neurophysiological improvements suggest this benefit is coming from improved transmission at neuromuscular junctions. However, whether NMJs are perturbed in the human disease is unknown. The best model for testing this before moving to patients is an hiPSC-derived nerve-muscle co-culture system where we can establish that motor neuron- muscle connectivity is indeed perturbed and that treatment with integrated stress response inhibitors improves function. Establishing this would make ISR inhibitors more translational and increase interest in CMT from companies developing such drugs. These more sophisticate co-culture systems and particularly those for evaluating NMJ connectivity, are beyond the current expertise of the Burgess lab. We therefore propose this re- training supplement request to train Dr. Timothy Hines in these approaches. Dr. Hines is an accomplished senior postdoc who will transition to an Associate Research Scientist position at JAX to do this work. We have assembled a team of local and external mentors to train Dr. Hines in these methods. With these skills, Dr. Hines will be well-positioned to find an independent position and secure NIH funding in the future. This supplement will benefit Dr. Hines’ professional development and the parent grant by making the experiments more translationally relevant.


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 = $2,353,584 )
2025	2025	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	2/27/2025	SUPPLEMENT FOR EXPANSION	$784,528
2025	2025	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	15	2/27/2025	EXTENSION WITH OR WITHOUT FUNDS	$784,528
2025	2025	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	16	6/4/2025	NON-COMPETING CONTINUATION	$784,528
2025	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	15	2/27/2025	EXTENSION WITH OR WITHOUT FUNDS	$259,216
2025	2021	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	2/27/2025	SUPPLEMENT FOR EXPANSION	-$259,216
														Subtotal = $2,353,584

Issue Date FY: 2024 ( Subtotal = $784,528 )
2024	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	7/23/2024	EXTENSION WITH OR WITHOUT FUNDS	$784,528
														Subtotal = $784,528

Issue Date FY: 2022 ( Subtotal = $3 )
2022	2020	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	1/11/2022	COMPETING CONTINUATION	$3
														Subtotal = $3

Issue Date FY: 2021 ( Subtotal = $277,780 )
2021	2021	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	8/26/2021	SUPPLEMENT FOR EXPANSION	$277,780
														Subtotal = $277,780

Issue Date FY: 2020 ( Subtotal = $2,825,120 )
2020	2020	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	8/11/2020	COMPETING CONTINUATION	$706,280
2020	2020	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	14	9/17/2020	COMPETING CONTINUATION	$2,118,840
														Subtotal = $2,825,120

Grand Total All Awards = $6,241,015

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The Genetics of the Neuromuscular Junction: Mechanisms and Disease Models

Award Number: R37NS054154

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: 08/01/2025

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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