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Exploring Wnt-Fzd signaling specificities

Award Number: R35GM134961
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Exploring Wnt-Fzd signaling specificities - Project Summary/Abstract: Cell-cell communication lies at the heart of evolution of multi-cellular life: cells send specific signals to instruct their neighbors to adopt fates distinct of their own. An important class of developmental signals is encoded by the Wnt gene family. Wnt proteins interact with their cognate receptors of the Frizzled (Fzd) family to control countless developmental processes, from establishing the polarity of a single cell within a tissue to specifying the anterior-posterior body axis of an organism. Deregulation of Wnt signaling can have catastrophic consequences, including embryonic lethality, birth defects, and disease. With their diverse and potent activities in development and stem cells, Wnt proteins hold great promise as potent tools in cell and tissue engineering. The long-term objective of our research is to gain a better understanding of how Wnt proteins and their downstream signaling events influence cell fate decisions, and thereby advance technologies and treatments that specifically target Wnt signaling. Over the past years, we have made important contributions to the development of Wnts as research-grade reagents to manipulate human pluripotent stem (hPS) cells and generate cell populations with potential therapeutic value. However, significant challenges need to be addressed before the full potential of Wnts as therapeutics can be realized. In particular, despite their potent activities, many Wnt proteins remain difficult to isolate in a biologically active and stable form. Furthermore, with 19 Wnts and over 20 Wnt receptors (including Fzd1-10, Lrp5/6, Ror1/2, etc.) encoded in the mammalian genome, it is unclear how signaling specificity is established. Finally, many current attempts to target Wnt signaling in clinical settings are highly non-specific and produce complications and adverse side effects. The goal for the next five years is to leverage an innovative technology developed in our laboratory that utilizes engineered Wnt agonists, called Wnt mimetics, which exhibit superior biochemical properties compared to native Wnt proteins. These Wnt mimetics will be tested for their effects in several settings, including hPS cell self-renewal and differentiation, organoid cultures and in whole animals (mice). Furthermore, the proposed research will explore a new paradigm for how Wnt signaling specificity is established in vivo, and thereby enable the development of tools and approaches that pinpoint individual Wnt signaling pathways. These experiments will allow us to test our hypothesis that selective engagement and activation of individual Wnt receptors and receptor complexes trigger distinct signaling outputs and biological effects. The proposed research will significantly advance the field of stem cell research and tissue engineering by establishing new tools and methods to manipulate Wnt signaling in vitro and in vivo. With its abundant roles in human disorders and diseases, a better understanding of Wnt signaling is essential for the development of novel therapies for currently incurable diseases.


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 = $0 )
2025	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	5	5/6/2025	NON-COMPETING CONTINUATION	$0
2025	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	5	11/8/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $395,000 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	5	12/11/2023	NON-COMPETING CONTINUATION	$355,501
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	5	6/24/2024	NON-COMPETING CONTINUATION	$39,499
														Subtotal = $395,000

Issue Date FY: 2023 ( Subtotal = $406,622 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	4	3/21/2023	NON-COMPETING CONTINUATION	$39,499
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	002	4	7/11/2023	SUPPLEMENT FOR EXPANSION	$11,622
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	1/25/2023	NON-COMPETING CONTINUATION	$355,501
														Subtotal = $406,622

Issue Date FY: 2022 ( Subtotal = $395,000 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	3	7/25/2022	NON-COMPETING CONTINUATION	$39,499
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	3	12/21/2021	NON-COMPETING CONTINUATION	$355,501
														Subtotal = $395,000

Issue Date FY: 2021 ( Subtotal = $654,266 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	2	1/6/2021	NON-COMPETING CONTINUATION	$403,589
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	002	2	9/16/2021	SUPPLEMENT FOR EXPANSION	$205,834
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	2	3/3/2021	NON-COMPETING CONTINUATION	$44,843
														Subtotal = $654,266

Issue Date FY: 2020 ( Subtotal = $403,819 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	12/17/2019	NEW	$403,819
														Subtotal = $403,819

Grand Total All Awards = $2,254,707

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Exploring Wnt-Fzd signaling specificities

Award Number: R35GM134961

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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