Wednesday, August 20, 2025 8/20/2025

Role of Fragile X Mental Retardation Protein on Gene Expression in Auditory Brainstem Development

Award Number: K08DC019416
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Role of Fragile X Mental Retardation Protein on Gene Expression in Auditory Brainstem Development - Fragile X Syndrome (FXS) is the most common heritable autism spectrum disorder and is associated with auditory features such as hypersensitivity to sound (hyperacusis). FXS is caused by the absence of Fragile X mental retardation protein (FMRP), which is known to bind specific mRNAs and repress their translation. Little is known about how FMRP impacts the central auditory pathway. We will study FMRP effects on gene expression in the auditory brainstem, using the well-established fmr1-knockout (KO) mouse model, which exhibits auditory hypersensitivity and seizures in response to loud noise. Although the well-established role of FMRP is translational repression, it has been shown recently in neurons that FMRP can also change the level of many mRNAs. Whether this occurs in the auditory brainstem is unknown. We have novel transcriptome data (unpublished) showing that the levels of many mRNAs that are known to be bound by FMRP, and to function in synaptic pathways, are decreased in the fmr1-KO cochlear nucleus. How this occurs is not known. Aim 1 will test the hypothesis that direct FMRP binding stabilizes the bound mRNA, but in the absence of FMRP, these mRNAs have decreased stability (and, therefore, decreased level). We will also determine if decreased stabilization of mRNA leads to decreased protein level or if it is offset by the loss of FMRP-mediated translational repression so as to manifest as increased protein level. Another possibility is that FMRP acts indirectly through translational repression of factors, such nonsense-mediated mRNA decay (NMD) factor, UPF1. Unpublished data from my research mentor’s lab has shown that induced pluripotent stem cells derived from FXS-patient fibroblasts manifest an abnormally high level of UPF1 (whose mRNA is bound by FMRP), resulting in hyperactivated NMD and, as a consequence, reduced levels of cellular NMD target mRNAs. Based on these data, Aim 2 will test the hypothesis that NMD is hyperactivated in fmr1-KO cochlear nucleus, leading to gene downregulation. Lastly, it is known that FMRP is involved in activity dependent processes. For example, dendritic localization of FMRP is increased with glutamatergic signaling and loss of afferent activity can blunt translational repression by FMRP. Aim 3 will test the hypothesis that the FMRP effects on gene expression are dependent on afferent activity. We will examine an inducible deafness mouse model to determine if it can phenocopy the fmr1-KO, indicating that afferent activity is required for FMRP function. The PI has extensive molecular biology experience, and with the guidance of a primary mentor who is a respected RNA biologist. The PI will master current RNA techniques and work towards becoming an independent investigator. Results will reveal how FMRP regulates genes important for auditory development and plasticity. The ultimate goal is to reveal potential therapeutic targets to treat auditory hypersensitivity and processing disorders. The mechanism leading to hyperacusis is poorly understood, and because it is not limited to FXS and affects up to 15% of the population, the study is relevant to the general population.


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 = $182,253 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Research Related to Deafness and Communication Disorders	000	6	3/19/2025	NON-COMPETING CONTINUATION	$182,253
														Subtotal = $182,253

Issue Date FY: 2024 ( Subtotal = $182,009 )
2024	2024	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Research Related to Deafness and Communication Disorders	004	5	3/8/2024	NON-COMPETING CONTINUATION	$182,737
2024	2023	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Research Related to Deafness and Communication Disorders	000	3	1/16/2024	NON-COMPETING CONTINUATION	-$125,280
2024	2023	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Research Related to Deafness and Communication Disorders	002	3	2/27/2024	NON-COMPETING CONTINUATION	-$12,506
2024	2023	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Research Related to Deafness and Communication Disorders	003	4	2/27/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$12,506
2024	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Research Related to Deafness and Communication Disorders	001	4	1/17/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$124,552
														Subtotal = $182,009

Issue Date FY: 2023 ( Subtotal = $183,213 )
2023	2023	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Research Related to Deafness and Communication Disorders	000	3	3/22/2023	NON-COMPETING CONTINUATION	$183,213
														Subtotal = $183,213

Issue Date FY: 2022 ( Subtotal = $183,679 )
2022	2022	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Research Related to Deafness and Communication Disorders	000	2	3/16/2022	NON-COMPETING CONTINUATION	$183,679
														Subtotal = $183,679

Issue Date FY: 2021 ( Subtotal = $184,137 )
2021	2021	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Research Related to Deafness and Communication Disorders	000	1	2/12/2021	NEW	$184,137
														Subtotal = $184,137

Grand Total All Awards = $915,291

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Role of Fragile X Mental Retardation Protein on Gene Expression in Auditory Brainstem Development

Award Number: K08DC019416

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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