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Selective targeting of matrix metalloproteinases for developing preterm labor therapeutics

Award Number: R21HD109743
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT We have shown that specific members of the matrix metalloproteinase family (MMP-2 and MMP-9) are overexpressed in preterm laboring myometrium and that these enzymes exacerbate contractile responses in human uterine smooth muscle. Therefore, MMP-2/9 may serve as therapeutic targets to block preterm labor. Tissue inhibitors of metalloproteinases (TIMPs) are endogenous MMP inhibitors with subnanomolar affinity. Considering multifaceted role of MMPs in cellular function, we aim to target specific MMPs (MMP-2/9), responsible for uterine contraction in patients with preterm labor, with high selectivity while avoiding interactions with other beneficial MMPs. Our central hypothesis is that selective TIMP protein-based therapeutics can be developed to promote uterine quiescence. We will use protein engineering techniques such as directed evolution to produce tocolytic drug candidates based on TIMP protein scaffold to treat preterm labor. In Aim 1, we will use directed evolution and yeast surface display to engineer TIMP-based protein scaffolds to improve binding selectivity toward MMP-2/9. In Aim 2, we will evaluate the ability of wild-type and engineered TIMPs to reduce contractions in human uterine tissue. These data are expected to be significant because they will provide the foundation for candidate drug testing in preclinical in vivo models of preterm labor.


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 = $187,308 )
2024	2024	BOARD OF REGENTS OF THE NEVADA SYSTEM OF HIGHER ED	1664 N VIRGINIA ST # 285	RENO	NV	89557	WASHOE	USA	Child Health and Human Development Extramural Research	000	2	2/21/2024	NON-COMPETING CONTINUATION	$168,578
2024	2024	BOARD OF REGENTS OF THE NEVADA SYSTEM OF HIGHER ED	1664 N VIRGINIA ST # 285	RENO	NV	89557	WASHOE	USA	Child Health and Human Development Extramural Research	001	2	5/2/2024	NON-COMPETING CONTINUATION	$18,730
														Subtotal = $187,308

Issue Date FY: 2022 ( Subtotal = $211,204 )
2022	2022	NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Child Health and Human Development Extramural Research	001	1	9/2/2022	NEW	$0
2022	2022	NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Child Health and Human Development Extramural Research	000	1	8/26/2022	NEW	$211,204
														Subtotal = $211,204

Grand Total All Awards = $398,512

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Selective targeting of matrix metalloproteinases for developing preterm labor therapeutics

Award Number: R21HD109743

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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