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Uncovering the Roles of Chaperonin CCT in Neural Health and Disease.

Award Number: F31NS130970
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: 02/07/2023
PERIOD OF PERFORMANCE END DATE: 02/06/2024

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Uncovering the Roles of Chaperonin CCT in Neural Health and Disease. - Project Summary/Abstract Protein homeostasis, or proteostasis, is critical to neuronal cellular and molecular processes and derangements in proteostasis machinery have been linked to neurodegenerative protein aggregates. This project will investigate roles of the Chaperonin-Containing TCP-1 (CCT) complex in regulating cytoskeletal modulation in both homeostatic and proteinopathic disease conditions and how those roles mechanistically impact dendrite development and maintenance. The two specific aims will (1) examine how CCT facilitates the formation of complex dendritic arbors through secondary regulation of microtubules both directly and indirect and (2) parse how CCT attenuates the accumulation of neuropathogenic protein aggregates in vivo and genetically interacts with mutant Ataxin and Huntingtin to preserve arbor morphology. CCT is a cytosolic multi-subunit chaperone that folds de novo proteins, misfolded proteins in the cytosol, and mutant aggregate-prone proteins commonly associated with neurodegenerative diseases such as Huntington’s Disease and Spinocerebellar Ataxia (SCA). We were first to demonstrate that individual CCT subunit mutants in Drosophila Class IV multidendritic sensory neurons caused severe reductions in dendritic branching. I have carried out further experiments showing that CCT mutants results in underlying changes to the dendritic cytoskeleton, especially disrupting microtubules. While it is well-established that CCT folds tubulin, whether and how CCT is influencing the assembly of microtubules through direct or indirect means is unknown. Furthermore, preliminary data reveals a putative relationship between Cullin1, a component of the SkpA-F-box-Cullin E3 ubiquitin ligase, and CCT in the regulation of microtubules. A common target of Cullin1 and CCT is TORC1, and thus, I propose to investigate the associated molecular pathway in the regulation of the dendritic cytoskeleton in cellular homeostasis. For these analyses, I will leverage our expertise in neurogenetics, phenotypic analyses, time-lapse 4D imaging, neuromorphometrics and drug pharmacology studies. I have also completed pilot studies that reveal reductions in dendritic branching due to expression of mutant Huntingtin and Ataxin proteins. CCT is known to interact with these mutant proteins in vitro and mitigate aggregation, but the relationship has not been examined in vivo in neurons. Using advanced imaging techniques including time-lapse imaging, expansion and super-resolution microscopy as well as traditional biochemical techniques like Western blot and co-immunoprecipitation, I will investigate the ameliorative effects of CCT on mutant protein aggregates in vivo and examine how the relationships that support dendritic formation in homeostasis are maintained or deranged in the context of disease. Beyond the goals of the research plan, my training goals include new technical training in advanced imaging/microscopy and protein biochemistry coupled to mentoring/teaching activities and career development activities/networking. I have assembled an expert team of scientific and technical advisors which coupled to institutional environment and research infrastructure will support and advance my overall training goals.


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 = -$20,265 )
2025	2023	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION INC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/20/2024	NEW	-$20,265
														Subtotal = -$20,265

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION INC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/17/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $41,294 )
2023	2023	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/1/2023	NEW	$40,352
2023	2023	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	2/13/2023	NEW	$0
2023	2023	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	2/13/2023	NEW	$942
														Subtotal = $41,294

Grand Total All Awards = $21,029

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Uncovering the Roles of Chaperonin CCT in Neural Health and Disease.

Award Number: F31NS130970

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: 02/07/2023

PERIOD OF PERFORMANCE END DATE: 02/06/2024

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