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Understanding fibrin degradation by matrix metalloprotease-1 at the single molecule level

Award Number: R15GM137295
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: 04/01/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2023

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Understanding fibrin degradation by matrix metalloprotease-1 at the single molecule level - Project Summary/Abstract Every year, ~900,000 Americans are diagnosed with complications from clot formation leading to ~300,000 deaths and ~$28 billion annual cost. The number of adults with clot-related complications are estimated to reach ~1.82 million by 2050. Blood clots form through the coagulation cascade and are part of the natural response to injury and cut, preventing loss of blood from severed blood vessels. However, the life-saving process of clot formation can become life-threatening if a blood vessel is blocked due to a clot. Indeed, clot-related pathologies including heart attack, stroke, and pulmonary embolism account for ~50% of all hospital deaths. Reperfusion, the act of restoring blood flow, with tissue plasminogen activator (tPA) is the gold standard treatment for ischemic stroke. Adverse side effects and cost of tPA motivate alternative approaches to treat clots. A major component of blood clots is crosslinked fibrin. Water-soluble fibrin monomers assemble into water-insoluble fibrin polymer, which makes them difficult to study using common biochemical assays. Human matrix metalloproteases (MMPs) present in blood have fibrinolytic activity and are therefore potentially alternative targets in blood clot management. MMPs are a family of 25 enzymes and are implicated in the majority of the top ten causes of death. MMP1 is the best studied member of the MMP family with a crystal structure available and details of its interaction with collagen known. We have strong evidence for fibrinolytic activity of MMP1, which is modulated by antibiotics and MMP9, another important MMP-family member that is upregulated in many disease. We propose to define the mechanism of fibrin degradation at the single molecule with synergistic applications of ensemble assays and molecular dynamics simulations.


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: 2024 ( Subtotal = -$4,658 )
2024	2022	TRUSTEES OF THE COLORADO SCHOOL OF MINES	1500 ILLINOIS ST	GOLDEN	CO	80401	JEFFERSON	USA	Biomedical Research and Research Training	000	1	11/30/2023	SUPPLEMENT FOR EXPANSION	-$4,658
														Subtotal = -$4,658

Issue Date FY: 2022 ( Subtotal = $50,141 )
2022	2022	TRUSTEES OF THE COLORADO SCHOOL OF MINES	1500 ILLINOIS ST	GOLDEN	CO	80401	JEFFERSON	USA	Biomedical Research and Research Training	000	1	7/14/2022	SUPPLEMENT FOR EXPANSION	$50,141
														Subtotal = $50,141

Issue Date FY: 2020 ( Subtotal = $366,928 )
2020	2020	TRUSTEES OF THE COLORADO SCHOOL OF MINES	1500 ILLINOIS ST	GOLDEN	CO	80401	JEFFERSON	USA	Biomedical Research and Research Training	000	1	3/24/2020	NEW	$366,928
														Subtotal = $366,928

Grand Total All Awards = $412,411

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Understanding fibrin degradation by matrix metalloprotease-1 at the single molecule level

Award Number: R15GM137295

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: 04/01/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2023

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