Selective targeting of matrix metalloproteinases for developing preterm labor therapeutics
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Principal Investigator: Maryam Raeeszadeh Sarmazdeh Organization: UNIVERSITY OF NEVADA RENO Fiscal Year: 2024 Award: $187,308 Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development 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. Terms: <72-kDa Gelatinase><72-kDa Type IV Collagenase><72kD type IV Collagenase><92-kDa Gelatinase><92-kDa Type IV Collagenase><Address><Affinity><Assay><Binding><Bioassay><Biochemical><Biological Assay><Birth><Body Tissues><Cell Function><Cell Physiology><Cell Process><Cellular Function><Cellular Physiology><Cellular Process><Data><Directed Molecular Evolution><Dose><Drugs><Engineering><Enzyme Gene><Enzymes><Family><Foundations><Future><Gelatinase A><Gelatinase B><Gelatinase Neutrophil><Goals><Human><Infant Mortality><Infant Mortality Total><Infection><Inflammatory><Inhibition of Matrix Metalloproteinases><Inhibition of Matrix Metalloproteinases Pathway><Intervention><Intervention Strategies><Involuntary Muscle><Libraries><MMP Inhibitor><MMP-2><MMP-9><MMP-9 Protein><MMPs><Macrophage Gelatinase><Matrix Metalloproteinase Inhibitor><Matrix Metalloproteinase-2><Matrix Metalloproteinase-9><Matrix Metalloproteinases><Mechanics><Medication><Metallopeptidases><Metalloproteases><Metalloproteinases><Mice><Mice Mammals><Mission><Modern Man><Molecular Interaction><Murine><Mus><Myometrial><Myometrial Contraction><NICHD><National Institute of Child Health and Human Development><National Institute of Children's Health and Human Development><Ocytocin><Oxytocin><Parturition><Pathway interactions><Patients><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Pregnancy Outcome><Pregnant Uterus><Premature Birth><Premature Labor><Premature Obstetric Labor><Prematurely delivering><Preterm Birth><Preterm Labor><Process><Production><Protein Engineering><Proteins><Public Health><Recombinant Oxytocin><Recombinants><Research><Research Priority><Role><Scaffolding Protein><Smooth Muscle><Subcellular Process><Surface><Techniques><Testing><Therapeutic><Therapeutic Agents><Tissue Engineering><Tissue Inhibitor of Metalloproteinases><Tissues><Tocolysis><Tocolytic Agents><Tocolytic Therapy><Tocolytic Treatment><Tocolytics><Toxic effect><Toxicities><Type V Collagenase><United States><Uterine Contraction><Uterine Muscle><Uterus><Variant><Variation><Woman><Yeasts><bioengineered tissue><cervical remodeling><combinatorial><death among infants><death in first year of life><death in infancy><death in infants><directed evolution><disparity in health><drug candidate><drug detection><drug testing><drug/agent><engineered tissue><experiment><experimental research><experimental study><experiments><genetic protein engineering><health disparity><human tissue><improved><in vivo><in vivo Model><infant death><infant demise><infantile death><inhibitor><interventional strategy><mechanic><mechanical><member><mortality in infants><myometrium><nano-molar><nanomolar><native protein drug><novel><overexpress><overexpression><pathway><perinatal health><pharmaceutical><pharmaceutical protein><pharmacologic><pre-clinical><preclinical><premature><premature childbirth><premature delivery><prematurity><preterm delivery><prevent><preventing><protein design><protein drug agent><protein-based drug><response><screening><screenings><side effect><social role><therapeutic protein><therapeutic target><womb>