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Investigating the pathomechanisms underlying Charcot-Marie-Tooth Disease

Award Number: F99NS129169
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: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Investigating the pathomechanisms underlying Charcot-Marie-Tooth Disease - PROJECT SUMMARY Charcot-Marie-Tooth (CMT) disease is a genetically and clinically heterogeneous group of inherited peripheral neuropathies that is characterized by damage to long motor and sensory axons. The overall goal of this project is to identify the molecular and cellular processes that are shared between different CMT genes to help address a common target for treatment for this currently incurable disease. Our lab extensively studies aminoacyl-tRNA synthetases (aaRS), the largest gene family involved in CMT, and discovered the nuclear function of one aaRS, TyrRS, was shown to be associated to CMT pathogenesis while acting as a transcriptional regulator under oxidative stress. Aim 1 sets out to understand how the nuclear aaRS function in oxidative stress response plays a role in mouse physiology and if it is the commonality between CMT-linked aaRS. Findings so far suggest nuclear TyrRS in mice leads to an increased metabolism and disruption in the auditory system. This proposal sets out to perform a longitudinal study to determine if the hearing loss is degenerative and where in the auditory pathway there is a defect (e.g., sensory epithelium, spiral ganglion, brainstem, midbrain) while also examining the molecular targets responsible using RNA-Sequencing on tissue samples. Additionally, we uncovered that CMT-linked aaRS share a similar nuclear localization response upon oxidative stress treatment in neuronal cells only. Aim 1 also sets out to investigate this apparent cell type specificity, examine more cell lines, and evaluate the factor responsible for the translocation property. More broadly, I want to understand the connection between multiple CMT genes and subtypes to have a holistic view of the cellular organelles and signaling pathways underlying CMT pathomechanisms. Therefore, in Aim 2 as a postdoctoral trainee I will study a range of CMT proteins across subtypes of varying phenotypes. Patient derived, induced pluripotent stem cells will be differentiated into two relevant CMT cell types for each mutant: motor neurons and Schwann cells. Because there is evidence suggesting mitochondrial defects and oxidative stress in some CMT subtypes, I will specifically investigate mitochondrial morphology, dynamics, and function using imaging and cell-based assays, as well as, exploring the levels of oxidate stress, stress-related damage, and potential pathways affected in CMT in a cell type specific manner. During this proposal, activities such as teaching, writing workshops, mastery of technical skills, and conference participation will be emphasized to equip me with the professional development needed for an independent career in neuroscience.


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 = $0 )
2025	2023	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $35,694 )
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/29/2023	NON-COMPETING CONTINUATION	$35,694
														Subtotal = $35,694

Issue Date FY: 2022 ( Subtotal = $34,752 )
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/27/2022	NEW	$34,752
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	6/14/2022	NEW	$0
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	6/14/2022	NEW	$0
														Subtotal = $34,752

Grand Total All Awards = $70,446

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Investigating the pathomechanisms underlying Charcot-Marie-Tooth Disease

Award Number: F99NS129169

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: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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