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Defining post-transcriptional gene regulation in FMRP-deficiency usingmiRNA:target chimeras

Award Number: R01MH129292
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: 11/30/2027

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Defining post-transcriptional gene regulation in FMRP-deficiency usingmiRNA:target chimeras - Fragile X Syndrome (FXS) is the most common monogenic cause of Autism spectrum disorder (ASD), a group of complex neurodevelopmental disorders characterized by core diagnostic impairments in social interactions and communication, restricted repetitive behaviors and interests, and an association with intellectual disability. FXS results from deficiency in expression of the FMR1 gene encoding Fragile X Mental Retardation Protein (FMRP). An early overgrowth of neurons and excessive immature synaptic contacts have been observed in brains of children with FXS, as well as in the Fmr1 KO mouse model. At a molecular level, aberrant excessive protein synthesis, with altered production of key synaptic proteins, is implicated in the atypical neural and synaptic overgrowth. While FMRP loss can lead to excessive protein synthesis, mechanisms altering the gene-target selectivity of protein synthesis to produce the distinct phenotypes of FMRP-deficiency are incompletely understood. MicroRNAs (miRNAS) are small RNAs which can selectively target gene transcripts for repression in the RNA- induced silencing complex (RISC). FXS has been linked to misregulation of miRNAs and miRNA-mediated gene repression for over 15 years, but broad knowledge of alterations in targeted transcripts has been lacking. We propose to carry out genome-wide quantitative comparisons of RISC-mediated gene targeting in the wildtype and FMRP-deficient setting using both mice and human neurons. Directed by preliminary data, we will investigate the candidate let-7 miRNA family to test the hypothesis that dysregulation of let-7 miRNA biogenesis in the Fmr1 KO mouse contributes to altered repression of pro-growth mRNAs and downstream behavioral and neuroanatomical phenotypes. A multipronged approach for mechanistic investigation and prioritizing gene targets and pathways from genome-wide assessments will be followed by intervention to assess the functional consequences for FXS-associated phenotypes with the goal of enhancing our understanding of FMRP function and providing new molecular targets for intervention in phenotypes resulting from deficiency of FMRP.


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 = $467,827 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Mental Health Research Grants	000	4	11/26/2025	NON-COMPETING CONTINUATION	$467,827
														Subtotal = $467,827

Issue Date FY: 2025 ( Subtotal = $475,802 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Mental Health Research Grants	001	3	9/23/2025	NON-COMPETING CONTINUATION	$71,371
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Mental Health Research Grants	000	3	12/9/2024	NON-COMPETING CONTINUATION	$404,431
														Subtotal = $475,802

Issue Date FY: 2024 ( Subtotal = $487,264 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Mental Health Research Grants	001	2	8/15/2024	NON-COMPETING CONTINUATION	$48,726
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Mental Health Research Grants	000	2	12/27/2023	NON-COMPETING CONTINUATION	$438,538
														Subtotal = $487,264

Issue Date FY: 2023 ( Subtotal = $483,989 )
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Mental Health Research Grants	000	1	12/16/2022	NEW	$483,989
														Subtotal = $483,989

Grand Total All Awards = $1,914,882

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Defining post-transcriptional gene regulation in FMRP-deficiency usingmiRNA:target chimeras

Award Number: R01MH129292

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: 11/30/2027

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