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Decoding and Targeting the Molecular Mechanisms of TRAF7/KLF4 Driver Mutations in Meningioma

Award Number: F32NS146048
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/24/2026
PERIOD OF PERFORMANCE END DATE: 08/23/2027

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Decoding and Targeting the Molecular Mechanisms of TRAF7/KLF4 Driver Mutations in Meningioma - PROJECT SUMMARY/ABSTRACT Meningiomas are the most common primary brain tumors in adults, yet there are no effective pharmacological treatments, and standard-of-care approaches such as surgical resection and radiation are associated with significant risks and morbidity. Recent genomic studies have identified recurrent mutations in TRAF7 and KLF4, which frequently co-occur in a subset of meningiomas, yet the molecular mechanisms driving tumorigenesis in these tumors remain poorly understood. This project aims to define how TRAF7/KLF4 mutations promote meningioma growth and to identify novel therapeutic strategies targeting these tumors. The specific aims of this study are to (1) elucidate the cooperative signaling between TRAF7 and KLF4 mutations in meningioma pathogenesis, (2) characterize how TRAF7 WD40 domain mutations alter its protein interactions and ubiquitination activity, and (3) evaluate the therapeutic potential of targeting downstream gene activation in TRAF7/KLF4-mutant meningiomas. I will use CRISPR-Cas9 precise gene editing to introduce TRAF7 and KLF4K409Q mutations into human meningeal cells and assess how these mutations affect KLF4 stability, apoptotic signaling, and secretory phenotype. I will perform biochemical assays to determine whether mutant TRAF7 fails to ubiquitinate KLF4, leading to its increased stability and neomorphic gene activation. Additionally, I will investigate how these mutations alter TRAF7-MEKK3 interactions and impact apoptotic pathways, as well as examine whether they disrupt primary cilia function, contributing to fluid secretion and edema. To explore TRAF7 interactors I will employ advanced proteomic approaches such as Probe-dependent Proximity Profiling (ProPPr) and Proximity & Orientation-Dependent tagging of Ubiquitin (Ub-POD). These findings will identify TRAF7 interactome and ubiquitome to identify which function of this protein is altered by WD40 domain mutation. Finally, I will evaluate the therapeutic potential of targeting the neomorphic KLF4K409Q gene set through targeting the previously identified and medically-relevant targets, GPER1 and VEGFA, in vitro and in vivo using both genetic and pharmaceutical methods. This research aligns with the mission of the NINDS by addressing the urgent need for targeted therapies for meningiomas, which can lead to severe neurological deficits, cognitive impairment, and treatment-resistant recurrence. By elucidating the molecular mechanisms of TRAF7/KLF4-driven tumorigenesis, this project will fill a critical gap in our understanding of meningiomas and identify new precision medicine strategies to improve patient outcomes. The findings from this study have the potential to transform the clinical management of meningiomas and inform broader therapeutic approaches for other disorders driven by TRAF7 dysregulation.


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 = $80,020 )
2026	2026	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/24/2026	NEW	$80,020
														Subtotal = $80,020

Grand Total All Awards = $80,020

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Decoding and Targeting the Molecular Mechanisms of TRAF7/KLF4 Driver Mutations in Meningioma

Award Number: F32NS146048

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/24/2026

PERIOD OF PERFORMANCE END DATE: 08/23/2027

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