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Engineering protease biomarkers to guide surgical therapy for vestibular schwannoma and Neurofibromatosis Type 2

Award Number: K08DC020761
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Engineering protease biomarkers to guide surgical therapy for vestibular schwannoma and Neurofibromatosis Type 2 - ABSTRACT Neurofibromatosis type 2 (NF2) is a profoundly devastating tumor predisposing syndrome characterized by multiple nervous system tumors that cause substantial debility for patients. The hallmark of NF2 is bilateral vestibular schwannomas (VS) which cause hearing loss, imbalance, brainstem compression and even death. Both NF2-associated and sporadic VS can develop aggressive cystic degeneration which result in rapid neurologic decline. There are no FDA-approved pharmacotherapies against cystic VS and surgery is the only treatment. However, surgical outcomes are highly variable, and surgery carries considerable morbidities including deafness, facial paralysis, brain injury and incomplete resection, due to significant peri-tumoral adhesions and reliance on imprecise visual cues during tumor dissection. Efforts are needed to identify biomarkers to classify aggressive VS and develop intraoperative tools to detect tumor cells, visualize the interface between tumor and cochlear/facial cranial nerves and improve the accuracy of surgical resection. This K08 career development award is designed to launch the principal investigator’s career as an independent surgeon scientist, whose goal is to understand mechanisms that underlie VS growth and cystic degeneration, identify molecular biomarkers to classify disease, and leverage nanotechnology tools to improve the precision of tumor surgery. The PI’s mentor (Krystof Bankiewicz) is a leader in delivering therapeutics to the central nervous system and translational research. The PI’s co-mentor (Long-Sheng Chang) is an expert in studying the NF2 tumor suppressor gene function in VS. Additional mentorship is provided by a research advisory committee of experts in nanoparticle delivery (Yizhou Dong), matrix metalloprotease and extracellular matrix biology (Jennifer Leight), and skull base surgery (Oliver Adunka), along with didactics and workshops at the Ohio State University and nationally. Previously, the PI utilized primary human VS cultures to develop nanoparticles that target VS and identified a matrix metalloproteinase whose activity was associated with poor surgical outcomes in VS. The proposed study will: 1) systematically identify proteases dysregulated in VS through spatial transcriptomic profiling; 2) engineer a library of nanomaterials to rapidly quantify VS protease activity and establish an activity-based tumor-classifying biomarker; 3) develop protease-sensing, tumor-targeted nanoparticles. Results from this work will elucidate mechanisms that regulate VS behavior and establish tools to enhance the accuracy of surgical resection, which could ultimately reduce treatment-associated morbidity, preserve cranial nerve function and improve outcomes for patients with this devastating disease. Furthermore, the principal investigator will obtain the training needed to transition into an independent physician scientist focusing on using nanotechnology to translate biological discoveries into new diagnostics and therapeutics for VS and NF2.


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 = $184,001 )
2026	2026	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Research Related to Deafness and Communication Disorders	000	4	1/16/2026	NON-COMPETING CONTINUATION	$184,001
														Subtotal = $184,001

Issue Date FY: 2025 ( Subtotal = $184,001 )
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Research Related to Deafness and Communication Disorders	000	3	12/18/2024	NON-COMPETING CONTINUATION	$184,001
														Subtotal = $184,001

Issue Date FY: 2024 ( Subtotal = $191,561 )
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Research Related to Deafness and Communication Disorders	000	2	1/5/2024	NON-COMPETING CONTINUATION	$191,561
														Subtotal = $191,561

Issue Date FY: 2023 ( Subtotal = $191,808 )
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Research Related to Deafness and Communication Disorders	001	1	2/22/2023	NEW	$13,781
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Research Related to Deafness and Communication Disorders	000	1	12/26/2022	NEW	$178,027
														Subtotal = $191,808

Grand Total All Awards = $751,371

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Engineering protease biomarkers to guide surgical therapy for vestibular schwannoma and Neurofibromatosis Type 2

Award Number: K08DC020761

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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