Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Actin-mediated regulation of organelle dynamics in Charcot-Marie-Tooth disease

Award Number: F32GM137580
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2022

Group Awards By:

View Award Description

Actin-mediated regulation of organelle dynamics in Charcot-Marie-Tooth disease - Project Summary Organelle dynamics profoundly affect the physiology of the cell and are regulated by interactions with the cytoskeleton. Alterations in organelle dynamics (i.e., inter-organelle and cytoskeletal contacts, fission, and mobility) are associated with a variety of human diseases, particularly neuropathies. Charcot-Marie-Tooth (CMT) disease is the most commonly inherited neuropathy and is caused by mutations in at least eighty different genes. Although the mutations that cause CMT are often in genes linked to altered organelle dynamics, questions remain regarding the pathogenic mechanism. Mitochondrial fission is mediated by the polymerization of actin at ER-mitochondria contact sites via the ER-anchored, actin polymerizing protein INF2. Dominant activating mutations in INF2 cause increased mitochondrial fission and excessive actin accumulation on mitochondria, which reduces mitochondrial mobility. Similar mutations in INF2 also cause CMT. Preliminary data show that 1) actin accumulates at fission sites of other organelles including endosomes, lysosomes, peroxisomes, and the Golgi, and 2) that CMT mutations in INF2 cause a reduction in endosome and lysosome mobility. This leads to the central hypothesis of this proposal: there is a conserved molecular mechanism regulating organelle fission and mobility mediated by actin cytoskeletal proteins at ER-organelle contact sites. Furthermore, it is proposed that reduction in organelle mobility specifically affects peripheral neurons due to the extreme length of these cells and hence may be a general pathogenic feature of CMT. The Specific Aims of this project are as follows: Aim 1 focuses on the role of INF2 in mitochondrial, endosomal, and lysosomal fission and how these processes are altered by mutations in INF2 that cause CMT. These studies will be carried out in primary human fibroblasts via live-cell imaging, including the use of a novel, innovative probe that specifically labels ER-associated actin. Experiments to assess organelle functions and to directly implicate actin polymerization in the phenotypes observed will also be performed. Aim 2 will be carried out in cultured primary mouse neurons in order to properly assess how alterations in organelle dynamics and mobility affect neuronal health. Deep learning-based image restoration will be used to achieve high spatiotemporal resolution imaging of organelle mobility. Aim 3 will include organelle and neuronal health assays in the context of disease-relevant models of CMT. Specifically, neurons derived from CMT patient fibroblasts and neurons from mice injected with AAVs directing expression of CMT- mutant INF2, MFN2, or RAB7A will be analyzed. Completion of these aims will provide mechanistic insight into the role of actin in organelle fission and mobility, how these processes are coupled, and test the novel hypothesis that CMT involves global disruption of mobility of multiple organelles. This will further our understanding of the pathogenic mechanism of CMT and perhaps other neurodegenerative disorders. The project will also enhance my scientific training by providing me with invaluable training in neurobiology and neurodegeneration, designing novel imaging probes, advanced imaging techniques, stem-cell based reprogramming, and mouse models.


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 = $0 )
2024	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	2	10/31/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $69,802 )
2022	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	2	11/29/2021	NON-COMPETING CONTINUATION	$68,562
2022	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	2	6/16/2022	NON-COMPETING CONTINUATION	$1,240
														Subtotal = $69,802

Issue Date FY: 2021 ( Subtotal = $66,390 )
2021	2021	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	002	1	2/9/2021	NEW	$1,080
2021	2021	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	1	12/16/2020	NEW	$0
2021	2021	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	12/16/2020	NEW	$65,310
														Subtotal = $66,390

Grand Total All Awards = $136,192

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Actin-mediated regulation of organelle dynamics in Charcot-Marie-Tooth disease

Award Number: F32GM137580

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2022

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer