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Designing technologies to visualize protease activity in cancer models

Award Number: R21GM143593
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: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2024

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Designing technologies to visualize protease activity in cancer models - PROJECT SUMMARY Cancer is a collection of diseases that are caused by the uncontrolled proliferation of cells. It is the second leading cause of death in the United States of America and approximately 40% of Americans will get diagnosed with cancer at some point in their life. Proteases, which are enzymes that cleave peptide bonds, play vital roles in many steps in cancer progression, including migration and metastasis. Drugs that target protease activity have entered clinical trials, however they were all unsuccessful. New anti-protease therapies are being developed with improved enzyme specificity to reduce unwanted side-effects. Thus increasing our understanding of protease activity in the tumor microenvironment is needed to bring these promising drugs to the clinic. The objective of this project is to develop biomolecular conjugates which can visualize protease activity within model tissues in order to understand how cancerous cells modulate the activity of other local cells. These conjugates combine nucleic acids and peptide such that a protease cleaving the peptide activates the nucleic acid for binding. This will be used quantify protease activity around individual cell types. Since nucleic acid hybridization is sequence-specific, multiple protease can be studied simultaneously within a single hydrogel. The conjugates will be coupled to the hydrogel using “click” chemistry. This enables the molecules to be added during cell culture in order to study protease activity at specified time points. These conjugates have been designed so that they can be made on automated synthesizers, and can be easily incorporated into most biomaterials platforms. This research plan includes two specific aims that were designed to develop protease-responsive conjugates, incorporate them into hydrogels, and visualize spatiotemporal protease activity in a model tissue. The first aim will develop nucleic acid-peptide conjugates which are able to bind fluorophore-labelled complementary strand only after they been “activated” by proteases. The second aim will incorporate these conjugates into hydrogels for simultaneous spatiotemporal visualization proteases in a hydrogels containing both cancerous and noncancerous cells in order to better understand metastatic processes. We hypothesize that cancer cells cultured with non-cancerous cells will have altered protease activity. This approach is powerful because it can be easily adapted by other labs, can be used for many proteases and incorporated into most biomaterial systems. Since proteases catalyze the cleavage of a peptide bond, they are especially useful for making stimuli-responsive therapies. Thus this research can help researchers across disciplines develop more effective biomedical interventions.


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 = -$1 )
2025	2022	LEHIGH UNIVERSITY	526 BRODHEAD AVE	BETHLEHEM	PA	18015	NORTHAMPTON	USA	Biomedical Research and Research Training	000	2	4/2/2025	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2022 ( Subtotal = $224,152 )
2022	2022	LEHIGH UNIVERSITY	526 BRODHEAD AVE	BETHLEHEM	PA	18015	NORTHAMPTON	USA	Biomedical Research and Research Training	000	2	8/8/2022	NON-COMPETING CONTINUATION	$224,152
														Subtotal = $224,152

Issue Date FY: 2021 ( Subtotal = $184,341 )
2021	2021	LEHIGH UNIVERSITY	526 BRODHEAD AVE	BETHLEHEM	PA	18015	NORTHAMPTON	USA	Biomedical Research and Research Training	000	1	8/11/2021	NEW	$184,341
														Subtotal = $184,341

Grand Total All Awards = $408,492

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Designing technologies to visualize protease activity in cancer models

Award Number: R21GM143593

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: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2024

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