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A Directed Evolution Approach to Affinity-Based Protein Delivery

Award Number: R21EB032112
ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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A Directed Evolution Approach to Affinity-Based Protein Delivery - PROJECT SUMMARY Tissue regeneration is a dynamic, carefully coordinated process in which many proteins and cell populations participate. Disruptions in the healing cascade caused by chronic disease or severe injury can easily impair tissue regeneration, resulting in injuries that do not heal. Our long-term goal is to design affinity-based hydrogels that can provide phased delivery of multiple therapeutic proteins to enhance tissue repair. We have developed a “bottom-up” modular approach to protein delivery, in which specific affinity interactions between small protein domains (i.e. binding partners) and therapeutic proteins are integrated into biomaterials to independently and predictably control the release of multiple proteins. We are using directed evolution of yeast surface display libraries to identify binding partners with high specificity and moderate affinities for proteins, to enable protein release over different timescales. We expect that our approach will more accurately recapitulate the natural, staggered presentation of multiple proteins during the healing cascade, providing the necessary combinations of proteins to activate key phases of the repair process. In Aim 1, we will evolve binding partners for therapeutic proteins using yeast surface display. We will characterize an assortment of affibodies specific to each therapeutic protein to generate a large diversity of orthogonal, protein-affibody affinity interactions. In Aim 2, we will use statistical modeling to optimize biomaterial properties to achieve desired protein release profiles. We will feed this information into COMSOL bio-transport models to predict protein delivery in vitro and in vivo. In Aim 3, we will synthesize hyaluronic acid hydrogels containing binding partners to investigate tunable co-delivery of multiple proteins in vitro and in vivo. Our modeling results will inform the design of biomaterials that enable the delivery of multiple proteins with distinct release profiles. In vitro protein release from hydrogels will be evaluated via ELISA. In vivo retention of fluorescently labeled proteins within implanted hydrogels will be evaluated using longitudinal live fluorescence imaging of rats. Ultimately, we expect to achieve independent control over the release of a wide range of therapeutic proteins relevant to tissue repair through orthogonal protein-material affinity interactions. We expect that our versatile biomaterial platform can be applied to the precise delivery of a broad range of proteins and will enable systematic investigation of the timing of protein presentation required for tissue healing. This work will lay the foundation to cultivate clinically-relevant strategies for stimulating robust tissue repair in multiple organ systems.


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 = -$1,328 )
2026	2023	UNIVERSITY OF OREGON	1776 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	3	11/20/2025	NON-COMPETING CONTINUATION	-$1,328
														Subtotal = -$1,328

Issue Date FY: 2023 ( Subtotal = $184,475 )
2023	2023	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	3	7/11/2023	NON-COMPETING CONTINUATION	$184,475
														Subtotal = $184,475

Issue Date FY: 2022 ( Subtotal = $189,730 )
2022	2022	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	2	6/7/2022	NON-COMPETING CONTINUATION	$189,730
														Subtotal = $189,730

Issue Date FY: 2021 ( Subtotal = $227,961 )
2021	2021	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	1	8/24/2021	NEW	$227,961
														Subtotal = $227,961

Grand Total All Awards = $600,838

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A Directed Evolution Approach to Affinity-Based Protein Delivery

Award Number: R21EB032112

ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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