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Understanding the effects of p97 protein-protein interactions on cellular functions using antibody-based inhibitors

Award Number: F32GM139242
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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Understanding the effects of p97 protein-protein interactions on cellular functions using antibody-based inhibitors - Project Summary/Abstract Protein-protein interactions (PPIs) connect various proteins to achieve critical cellular functions. For instance, the ubiquitously expressed protein valosin-containing protein (VCP/p97) is involved in multiple biological events via PPIs, maintaining protein homeostasis in different organelles. Considering the participation of multiple proteins in each process, it will be fundamentally beneficial to systematically decipher the p97 PPI network. Proteomics studies have demonstrated that the p97 PPI network is highly dynamic. However, a comprehensive set of p97 PPIs, their functions, and protein substrates has been elusive. The overall goal of this proposal is to dissect the p97 PPI network using engineered antibody inhibitors, providing fundamental insights on the modulation of specific cellular functions through the regulation of p97 PPI. Till now, at least 30 adaptor proteins of p97 have been discovered. In general, the roles of these adaptor proteins are described in broad terms (e.g., “membrane remodeling”). What are the specific substrates or differentiating functions of these adaptors, and do they work independently or together? Our central hypothesis is that, by developing p97/adaptor specific inhibitors, the distinctive functions of each adaptor can be defined within the p97 PPI network. FAS-associated factor 1 (FAF1), an important adaptor protein of p97, will be employed as the primary example to develop the technology for the modulation of p97 PPI. FAF1 is of particular interest, as it has been shown to be involved in the regulation of chromatin-associated degradation and NF-κB signaling. Notably, such processes are found to involve both p97 and FAF1, and it is not clear whether all functions of FAF1 are p97-dependent. To test the hypothesis, antibody fragments will be engineered for the p97-binding (UBX) domain on FAF1, blocking FAF1's interaction with p97 and leaving the rest of FAF1's and p97's activities intact. Unlike the gene knockdown/knockout strategy, the proposed strategy will directly probe the role of the PPI without requiring the deficiency of involved proteins, reflecting the real-time contribution of the interaction of interest. The role of p97-FAF1 interaction will be evaluated in both chromatin- associated degradation process and NF-κB signaling. These two processes involve different domains of FAF1 for regular function, facilitating the assessment of p97 substrate specificity during the p97-FAF1 interaction. The goal of this proposal is to establish an experimental model to dissect p97 PPIs, exploring the linkages between p97 PPIs and FAF1's various cellular functions. This approach is broadly applicable to dissect the role of each adaptor protein, shedding light on the entire p97 interactome. The outcome of the proposed research will include a validated approach to modulate each p97/adaptor complex and can be extended to other important PPIs. Overall, these studies may also provide a foundation for development of therapies aimed at modulating specific properties of FAF1 and p97 in cell-cycle progression and immune-cell activation.


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 = -$427 )
2025	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	3	11/27/2024	NON-COMPETING CONTINUATION	-$427
														Subtotal = -$427

Issue Date FY: 2023 ( Subtotal = $71,792 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	3	1/25/2023	NON-COMPETING CONTINUATION	$69,802
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Biomedical Research and Research Training	001	3	2/10/2023	NON-COMPETING CONTINUATION	$1,990
														Subtotal = $71,792

Issue Date FY: 2022 ( Subtotal = $67,582 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	2	1/7/2022	NON-COMPETING CONTINUATION	$66,390
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Biomedical Research and Research Training	001	2	6/10/2022	NON-COMPETING CONTINUATION	$1,192
														Subtotal = $67,582

Issue Date FY: 2021 ( Subtotal = $65,994 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Biomedical Research and Research Training	001	1	2/11/2021	NEW	$1,068
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Biomedical Research and Research Training	002	1	2/11/2021	NEW	$0
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	1	1/19/2021	NEW	$64,926
														Subtotal = $65,994

Grand Total All Awards = $204,941

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Understanding the effects of p97 protein-protein interactions on cellular functions using antibody-based inhibitors

Award Number: F32GM139242

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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