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Illuminating Notch receptor-ligand selectivity through structure-guided protein engineering

Award Number: R35GM133482
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: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2030

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Illuminating Notch receptor-ligand selectivity through structure-guided protein engineering - PROJECT SUMMARY Overall vision of the research program. My lab uses structure-guided engineering to reprogram receptor signaling for biomedical applications. By exploring the structural biology of cell surface receptors, our goal is to uncover novel strategies for engineering customizable signaling outputs. My research program largely focuses on receptor families that influence the development or maturation of stem cells. The Notch signaling pathway controls several aspects of stem cell and immune cell development, and my team has spent several years illuminating the structural biology of Notch signaling complexes. Additionally, we are developing several tools to turn Notch signaling “on” or “off” in desired tissues. We have also expanded our structural studies to include proteins that mediate crosstalk between developmental signaling pathways and complexes between emerging immune inhibitory receptors and their ligands. Overview of research in the laboratory. Our current research is focused on two major areas. The first is the development of biotechnological toolkits that can fine-tune receptor signaling depending on cellular context. Using the Notch pathway as a model system, we are establishing design principles for tissue-specific activators or inhibitors of receptor signaling. For the second area, we are studying the molecular basis for crosstalk between developmental signaling pathways. We have identified multiple non-canonical ligands of Notch and TGF-β family receptors that regulate signaling through both pathways. Our structure-function studies of these complex regulatory networks will expand our understanding of developmental signaling and illuminate new opportunities for therapeutic intervention. Goals for the next five years. Our goals are to: (i) assess the ability of Notch-modulating biologics to influence immune and stem cell biology in various biological systems; (ii) elucidate the molecular mechanisms by which non-canonical Notch ligands regulate developmental signaling; and (iii) identify novel extracellular Notch binding partners and determine their effect on Notch signaling activity. These research areas will provide a strong foundation for our continued research in developmental signaling, which will enable us to engineer novel biotechnologies for regenerative medicine and therapeutic development.


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 = $463,375 )
2025	2025	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Biomedical Research and Research Training	003	6	3/6/2025	COMPETING CONTINUATION	$61,632
2025	2025	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Biomedical Research and Research Training	000	6	1/16/2025	COMPETING CONTINUATION	$463,375
2025	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Biomedical Research and Research Training	001	5	3/6/2025	NON-COMPETING CONTINUATION	-$58,549
2025	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Biomedical Research and Research Training	002	5	3/6/2025	SUPPLEMENT FOR EXPANSION	-$3,083
														Subtotal = $463,375

Issue Date FY: 2023 ( Subtotal = $452,645 )
2023	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Biomedical Research and Research Training	000	5	6/26/2023	NON-COMPETING CONTINUATION	$430,000
2023	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Biomedical Research and Research Training	001	5	6/27/2023	SUPPLEMENT FOR EXPANSION	$22,645
														Subtotal = $452,645

Issue Date FY: 2022 ( Subtotal = $516,057 )
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Biomedical Research and Research Training	002	4	6/17/2022	SUPPLEMENT FOR EXPANSION	$54,351
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Biomedical Research and Research Training	001	4	6/16/2022	NON-COMPETING CONTINUATION	$430,000
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Biomedical Research and Research Training	000	3	11/26/2021	SUPPLEMENT FOR EXPANSION	$31,706
														Subtotal = $516,057

Issue Date FY: 2021 ( Subtotal = $514,384 )
2021	2021	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Biomedical Research and Research Training	000	3	6/10/2021	NON-COMPETING CONTINUATION	$430,000
2021	2021	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Biomedical Research and Research Training	001	3	7/14/2021	SUPPLEMENT FOR EXPANSION	$84,384
														Subtotal = $514,384

Issue Date FY: 2020 ( Subtotal = $430,000 )
2020	2020	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Biomedical Research and Research Training	000	2	6/11/2020	NON-COMPETING CONTINUATION	$430,000
														Subtotal = $430,000

Issue Date FY: 2019 ( Subtotal = $344,000 )
2019	2019	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Biomedical Research and Research Training	000	1	8/13/2019	NEW	$344,000
														Subtotal = $344,000

Grand Total All Awards = $2,720,461

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Illuminating Notch receptor-ligand selectivity through structure-guided protein engineering

Award Number: R35GM133482

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: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2030

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