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Mechanisms of Genome Architecture Regulation in Motor Learning

Award Number: R01NS123285
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: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Mechanisms of Genome Architecture Regulation in Motor Learning - The goals of the proposed research are to elucidate mechanisms of genome organization during neuronal activity in vivo and determine the roles of these mechanisms in learning and memory. We recently discovered that the sensory experience of animals controls the remodeling of neuronal genome architecture in the brain. The rapid induction of local genomic interactions between gene regulatory enhancers and promoters drives the upregulation of activity-dependent gene expression to promote motor learning. However, hundreds of genes are downregulated with neuronal activity in vivo, a finding that has been observed in multiple brain areas with unknown mechanisms and functions. This raises fundamental questions of what are the mechanisms that control activity-dependent transcriptional repression and what are the functions of these large genetic programs in motor learning. In this grant proposal, we will interrogate potential molecular mechanisms and biological functions of 3D genome organization at multiple scales in the control of gene repression. First, we will determine if neuronal activity might trigger sequence-specific transcription factors to remodel local genome architecture including between gene regulatory enhancers and promoters. Based on our findings, we will test the hypothesis that regulation of brain-enriched transcription factors triggers the breaking of enhancer-promoter interactions in the presence of neuronal activity to repress gene transcription. Furthermore, we will also test the hypothesis that local genome architecture maintained by these transcription factors play a critical role for motor learning in mice. These experiments will shed light on molecular mechanisms that dynamically regulate local genome architecture in the brain. Second, we will determine if remodeling of long-range genomic interactions including interactions between different chromosomes might regulate activity-dependent gene repression. Based on our preliminary findings, we will test the hypotheses that 1) in unstimulated neurons, genes form inter-chromosomal interactions with specific nuclear bodies involved in active transcription and 2) weakening of gene interactions with these nuclear bodies during neuronal activity attenuates gene expression. In addition, we will also test the hypothesis that these nuclear bodies found in adult neurons play specific roles in the acquisition or expression of motor memories in mice. These experiments will illuminate the roles of brain-enriched nuclear bodies in transcription and long-term memory. The proposed research will potentially advance our understanding of genome organization principles at both local and long-range genomic scales in the control of neural circuit refinement and adaptive changes in organismal behavior. Because mutations of genome architectural proteins and synaptic proteins are linked to disorders of cognition in humans, our research will also provide an integrated view on how sensory experiences orchestrate processes from the cell nucleus to the synapse to ensure a plastic and healthy brain.


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 = $418,178 )
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	7/17/2025	NON-COMPETING CONTINUATION	$418,178
														Subtotal = $418,178

Issue Date FY: 2024 ( Subtotal = $405,633 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/29/2024	NON-COMPETING CONTINUATION	$405,633
														Subtotal = $405,633

Issue Date FY: 2023 ( Subtotal = $415,538 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/1/2023	NON-COMPETING CONTINUATION	$415,538
														Subtotal = $415,538

Issue Date FY: 2022 ( Subtotal = $415,538 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/4/2022	NON-COMPETING CONTINUATION	$415,538
														Subtotal = $415,538

Issue Date FY: 2021 ( Subtotal = $414,700 )
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/1/2021	NEW	$414,700
														Subtotal = $414,700

Grand Total All Awards = $2,069,587

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Mechanisms of Genome Architecture Regulation in Motor Learning

Award Number: R01NS123285

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: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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