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Novel Roles of TAZ and YAP in DNA Damage Repair with 3D Genome Organization and the Therapeutic Resistance in Glioblastoma

Award Number: R01NS127922
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/03/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Novel Roles of TAZ and YAP in DNA Damage Repair with 3D Genome Organization and the Therapeutic Resistance in Glioblastoma - PROJECT SUMMARY Glioblastoma (GBM) is an aggressive type of brain cancer that arises de novo and is therapy resistant. A key contributor to poor outcomes in GBM is a subpopulation of cells called glioma stem-like cells (GSCs) that evade conventional cytotoxic therapies and repopulate as recurrent tumors. A fuller understanding of the molecular mechanisms underlying the biology and therapy resistance of GSCs is required. Our group has shown that TAZ, a transcriptional co-factor is highly expressed in about 70% of GBMs. TAZ and its paralog YAP are oncogenic drivers of brain tumor progression. GSCs overexpressing TAZ undergo a proneural to mesenchymal subtype transition. TAZ driven cell fate change is accompanied by aggressive behavior such as increased grade, necrosis and radio-resistance. Silencing YAP/TAZ ablates tumor growth by activating neurogenic programs, thus making these proteins attractive therapeutic targets. Although the oncogenic functions of YAP/TAZ are well established in GBM, the exact molecular mechanisms underlying cell fate transition and their contribution to therapy resistance are not fully understood. We have now accumulated substantial evidence to pinpoint a direct role for YAP/TAZ in DNA damage response pathway, a network of proteins that sense and repair DNA lesions in response to ionizing radiation (IR) treatments. YAP/TAZ also cause by enhancer reprogramming and recruitment of distinct molecular complexes in proneural and mesenchymal gene enhancers, which offers protection of DNA damage vulnerable regions of the genome. In this proposal, we will deeply investigate the molecular mechanisms underlying YAP/TAZ driven control of neurogenic programs and radio-resistance using both conventional and state-of-the-art molecular, cellular and biochemical approaches. Importantly, we will evaluate the therapeutic benefit of novel pharmacological inhibitors of the YAP/TAZ in combination with IR using pre-clinical models of GBM. Successful completion of these studies will not only unravel the mechanistic underpinnings behind neuronal differentiation and DNA damage repair in GBM, but also inform the development of next generation of clinical trials for GBM.


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 = $439,965 )
2025	2025	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	5/29/2025	NON-COMPETING CONTINUATION	$439,965
2025	2023	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/22/2025	NEW	$0
														Subtotal = $439,965

Issue Date FY: 2024 ( Subtotal = $427,263 )
2024	2024	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	7/26/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$427,263
2024	2023	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/26/2024	NEW	$0
														Subtotal = $427,263

Issue Date FY: 2023 ( Subtotal = $455,465 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/21/2023	NEW	$455,465
														Subtotal = $455,465

Grand Total All Awards = $1,322,693

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Novel Roles of TAZ and YAP in DNA Damage Repair with 3D Genome Organization and the Therapeutic Resistance in Glioblastoma

Award Number: R01NS127922

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/03/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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