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Regulation and function of human neural circular RNAs

Award Number: R01NS118819
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: 03/15/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Regulation and function of human neural circular RNAs - Project Summary Circular RNAs (circRNAs) are a novel class of covalently closed RNA species derived from “back splicing” of pre-mRNAs. Mounting evidence suggests the essential roles of circRNAs in governing healthy brain development and their abnormalities in neurological and neuropsychiatric disorders. Many circRNAs are unique and highly abundant in the human brain, which are thought to underlie the sophisticated function of human brains and the fragility of various brain diseases. Mechanistically, circRNAs can function through sponging microRNAs or RNA-binding proteins, which broadly regulate numerous biological pathways. Our current knowledge of molecular mechanisms that regulate circRNA biogenesis in the human brain is still in its infancy. In particular, circRNA biology in human glial cells are poorly understood. Whether neurons and glia cells possess distinct circRNA landscapes and downstream interactomes remain entirely unknown. The biological functions of circRNAs in governing brain development and modulating lesion repair are vastly elusive. These prevailing knowledge gaps limit the current understanding of the complex etiology of many brain diseases. Our long-term goals are to elucidate the regulation and function of circRNAs in healthy and diseased brains, which may help to develop novel therapeutics against brain illnesses. In this application, we focus on circRNA biology in oligodendroglia (OL). OLs are responsible for myelination of the central nervous system and affected in numerous diseases, represented by multiple sclerosis and schizophrenia. Our preliminary data revealed that the RNA-binding protein QKI advances biogenesis of a human OL circRNA, which can promote differentiation of human and rodent OLs. We established state-of-the-art technical platforms to identify circRNA landscapes and interactomes in human OL and neurons. We hypothesize that human circRNAs play essential roles in controlling OL and myelin development, and QKI mediates developmental signals to enhance human OL circRNA biogenesis. In Aim 1, we will determine how QKI regulates OL circRNA biogenesis to advance OL differentiation. In Aim 2, we will determine developmental regulation of human OL circRNA landscapes, downstream pathways, and mechanisms of circRNA action in OLs from multiple platforms with integrated analyses. In Aim 3, we will explore whether human OL circRNA pathways can promote OL lineage development in human induced pluripotent stem cell (iPSC)-derived oligodendrocyte spheres (hOLS) or myelin lesion repair in a well-established mouse model. Findings from these studies will provide novel insights on fundamental rules governing human OL function and myelin repair.


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 = $0 )
2026	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	10/8/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $472,174 )
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/16/2024	NON-COMPETING CONTINUATION	$472,174
														Subtotal = $472,174

Issue Date FY: 2024 ( Subtotal = $522,020 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/15/2024	NON-COMPETING CONTINUATION	$37,672
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/26/2024	NON-COMPETING CONTINUATION	$484,348
														Subtotal = $522,020

Issue Date FY: 2023 ( Subtotal = $548,449 )
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/7/2023	NON-COMPETING CONTINUATION	$548,449
														Subtotal = $548,449

Issue Date FY: 2022 ( Subtotal = $561,145 )
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/24/2022	NON-COMPETING CONTINUATION	$56,114
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/22/2021	NON-COMPETING CONTINUATION	$505,031
														Subtotal = $561,145

Issue Date FY: 2021 ( Subtotal = $571,725 )
2021	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/2/2021	NEW	$571,725
														Subtotal = $571,725

Grand Total All Awards = $2,675,513

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Regulation and function of human neural circular RNAs

Award Number: R01NS118819

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: 03/15/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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