The overall long-term objectives of this research are to elucidate mechanisms by which cell surface metalloproteinases and their secreted counterparts are regulated and interact, activate and degrade peptides and other proteins at the cell surface, as well as to define the physiological and pathological roles of these proteases in diseases such as diabetes mellitus and cancer. My approach has been to identify and characterize cell-associated proteinases and mechanisms used by living systems to degrade proteins and peptides according to the metabolic needs of the organism. The work has led to the discovery of meprins, unique mammalian metalloproteinases, and has provided fundamental information about the activity, structural characteristics, expression patterns, genes, and factors that determine secretion, retention in the endoplasmic reticulum, or proteasomal degradation of these complex and highly regulated enzymes. Our hypothesis is that meprins have a role in processing biologically active molecules such as gastrin and cholecystokinin, as well as cell-associated and extracellular proteins (membrane proteins, extracellular matrix proteins, and chemokines). In the next period, it is proposed to: (1) determine the physiological and pathological consequences of disrupting the meprin beta gene in mice, (2) disrupt the meprin alpha gene, and produce knockout mice for this subunit and double knockout mice for the alpha/beta genes, (3) define further physiological substrates for meprin mouse and human isoforms and the effects of metalloproteinase inhibitors, and to design potent inhibitors, and (4) determine structural factors critical for oligomerization and for enzymatic activity against polypeptides. The development of the meprin beta knockout mouse has provided a unique resource for the investigation of renal and intestinal disease. The multidomain, oligomeric meprin proteins provide a fascinating system to investigate regulation and activity of metalloproteinases that act at or near the cell surface. The studies will establish functions of meprins in developing, young and mature mice, and in cancer, inflammation and renal disease, and factors critical to regulating the enzymes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Metabolism Study Section (MET)
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Laughlin, Maren R
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Pennsylvania State University
Schools of Medicine
United States
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Bylander, John E; Ahmed, Faihaa; Conley, Sabena M et al. (2017) Meprin Metalloprotease Deficiency Associated with Higher Mortality Rates and More Severe Diabetic Kidney Injury in Mice with STZ-Induced Type 1 Diabetes. J Diabetes Res 2017:9035038
Keiffer, Timothy R; Bond, Judith S (2014) Meprin metalloproteases inactivate interleukin 6. J Biol Chem 289:7580-8
Jefferson, Tamara; Auf dem Keller, Ulrich; Bellac, Caroline et al. (2013) The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin ? and ADAM10. Cell Mol Life Sci 70:309-33
Bao, Jialing; Yura, Renee E; Matters, Gail L et al. (2013) Meprin A impairs epithelial barrier function, enhances monocyte migration, and cleaves the tight junction protein occludin. Am J Physiol Renal Physiol 305:F714-26
Garcia-Caballero, Agustin; Ishmael, Susan S; Dang, Yan et al. (2011) Activation of the epithelial sodium channel by the metalloprotease meprin * subunit. Channels (Austin) 5:14-22
Banerjee, Sanjita; Jin, Ge; Bradley, S Gaylen et al. (2011) Balance of meprin A and B in mice affects the progression of experimental inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 300:G273-82
Ongeri, Elimelda Moige; Anyanwu, Odinaka; Reeves, W Brian et al. (2011) Villin and actin in the mouse kidney brush-border membrane bind to and are degraded by meprins, an interaction that contributes to injury in ischemia-reperfusion. Am J Physiol Renal Physiol 301:F871-82
Jefferson, Tamara; ?auševi?, Mirsada; auf dem Keller, Ulrich et al. (2011) Metalloprotease meprin beta generates nontoxic N-terminal amyloid precursor protein fragments in vivo. J Biol Chem 286:27741-50
Banerjee, S; Oneda, B; Yap, L M et al. (2009) MEP1A allele for meprin A metalloprotease is a susceptibility gene for inflammatory bowel disease. Mucosal Immunol 2:220-31
Sun, Qi; Jin, Hong-Jian; Bond, Judith S (2009) Disruption of the meprin alpha and beta genes in mice alters homeostasis of monocytes and natural killer cells. Exp Hematol 37:346-56

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