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Analysis and Engineering of Cell Signaling

Award Number: R35GM136309
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: 05/01/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2031

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Analysis and Engineering of Cell Signaling - PROJECT SUMMARY This MIRA renewal application builds upon the work that my laboratory has conducted under the initial MIRA to develop and apply foundational methods for analyzing and engineering cell signaling in human health. The overall vision of our research program is to create enabling tools to uncover more detailed mechanistic understanding of signaling processes that can further facilitate the design of more effective therapies. The broad goals for the next five years are to develop new experimental and computational methodologies that can provide novel insights into the fundamental molecular mechanisms of receptor-ligand interactions, with an emphasis on proteins/interactions that are difficult to study due to their poor biophysical properties, combinatorial binding possibilities arising from multivalency, or complexities arising from cell-bound ligands (i.e., cell-cell interactions). For receptors with poor biophysical properties, such as integral membrane proteins, there are limited methods for high-throughput characterization of the ligands for such receptors since these receptors often require the native cell machinery and/or plasma membrane for proper synthesis, folding, and function. We propose to develop a methodology that leverages the power of directed evolution to rapidly map sequence/function relationships for natural ligands while also enabling engineering of novel binders to these complex yet clinically important targets. For multivalent and multispecific ligands, a key challenge is to enumerate the full combinatorial binding possibilities to multivalent targets and predict binding dynamics, which we incorporated into a new mechanistic model of multivalent binding during our prior support. Here, we propose to extend these efforts to understand how multivalent and multispecific ligand binding dynamics are further altered by binding to cell- surface targets, which will be clinically important for maximizing the efficacy and selectivity of promising new classes of multivalent and multispecific therapeutics. Extending the study to binding on cells requires additional consideration of cell-surface receptor dynamics such as mobility and internalization, which we will incorporate into our mechanistic modeling framework and also test experimentally. Finally, we propose to elucidate design principles for engineering ligand-receptor signaling when the ligand and the receptor exist on two distinct cell types. The nature of this cell-cell dose-response profile is essential for basic developmental processes (and their dysregulation) as well as the design of new therapeutic cells with improved efficacy and specificity. Collectively, advances in these areas of cell signaling will provide essential new tools for answering fundamental biological questions relevant to human health while also facilitating the design of novel molecular and cellular therapeutics for the treatment of a range of 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: 2026 ( Subtotal = $416,591 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Biomedical Research and Research Training	001	6	3/12/2026	COMPETING CONTINUATION	$416,591
2026	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Biomedical Research and Research Training	000	5	2/19/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $416,591

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	5	11/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $373,641 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	001	5	7/15/2024	NON-COMPETING CONTINUATION	$37,365
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	5	4/3/2024	NON-COMPETING CONTINUATION	$336,276
														Subtotal = $373,641

Issue Date FY: 2023 ( Subtotal = $373,641 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	4	4/19/2023	NON-COMPETING CONTINUATION	$373,641
														Subtotal = $373,641

Issue Date FY: 2022 ( Subtotal = $373,641 )
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	3	4/21/2022	NON-COMPETING CONTINUATION	$373,641
														Subtotal = $373,641

Issue Date FY: 2021 ( Subtotal = $373,266 )
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	2	4/1/2021	NON-COMPETING CONTINUATION	$373,266
														Subtotal = $373,266

Issue Date FY: 2020 ( Subtotal = $371,393 )
2020	2020	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	1	4/20/2020	NEW	$371,393
														Subtotal = $371,393

Grand Total All Awards = $2,282,173

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Analysis and Engineering of Cell Signaling

Award Number: R35GM136309

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: 05/01/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2031

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