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Epigenetic regulation of Cdk5 in cognition and emotion

Award Number: R01MH126027
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 10/31/2027

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Epigenetic regulation of Cdk5 in cognition and emotion - PROJECT SUMMARY Negative valence states can be modeled in mice using fear conditioning and reward seeking (an example of frustrative nonreward). Such states lead to transcriptional aberrations at the level of both individual genes and genome-wide; these changes are also sexually dimorphic. One gene of considerable interest is cyclin-dependent kinase 5 (Cdk5). While most prior studies have focused on the mechanisms of Cdk5 protein activation and signaling in stress-evoked behavior, we recently reported that cocaine exposure and fear conditioning lead to transcriptional regulation of Cdk5 in male mouse brain. This proposal will directly examine the connection between Cdk5 gene activation and Cdk5 protein activity. Furthermore, there is emerging evidence that Cdk5-associated histone modifications correlate with drug-, and fear-induced Cdk5 expression. The current proposal explores the functional relevance of stress-induced histone modifications at the murine Cdk5 locus across multiple behavioral paradigms using the innovative approach of locus-specific epigenetic editing. This approach allows us to recapitulate endogenous mechanisms of gene expression, avoiding non-physiologically relevant changes in protein expression resulting from traditional knockout or overexpression. Furthermore, we apply cell-type specific analyses to elucidate Cdk5 function in brain regions across the corticostriatal-limbic circuitry in the regulation of negative valence states. This proposal will examine the direct functional relevance of sex-specific, epigenetic regulation of Cdk5 by fear conditioning (Aim 1) and cocaine seeking during abstinence (Aim 2) using targeted epigenetic editing. Sex- and region- specific phosphoproteomic profiling will be applied to define relevant Cdk5 targets. Identification of the precise transcriptional and epigenetic mechanisms by which stress regulates specific gene expression is critical for the development of targeted antidepressant treatments.


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 = $507,376 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	3	11/5/2024	NON-COMPETING CONTINUATION	$507,376
														Subtotal = $507,376

Issue Date FY: 2024 ( Subtotal = $525,038 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	2	10/17/2023	NON-COMPETING CONTINUATION	$472,534
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	001	2	5/15/2024	NON-COMPETING CONTINUATION	$52,504
														Subtotal = $525,038

Issue Date FY: 2023 ( Subtotal = $499,571 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	1	12/28/2022	NEW	$499,571
														Subtotal = $499,571

Grand Total All Awards = $1,531,985

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Epigenetic regulation of Cdk5 in cognition and emotion

Award Number: R01MH126027

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 10/31/2027

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