serpins

..These findings indicate that vaspin exerts an insulin-sensitizing effect targeted toward WATs in states of obesity...

SERPINB3 (Squamous Cell Carcinoma Antigen, SCCA1) is a member of the ov-serpins, a serine protease inhibitors family expressed in many cell types including normal epithelium, leukocytes, tumors of epithelial origin and primary liver ..

..Detailed functional analysis revealed that both serpins interfered with all three pathways of the human complement system at different stages of their activation...

b>Serpins have been studied as a distinct protein superfamily since the early 80s...

..Inhibitory regulation of the proteinases by serpins and association of the proteinase homologs with a bacteria-binding lectin are important for ensuring a localized ..

..In conclusion, our data indicate that induction of human vaspin mRNA expression in adipose tissue is regulated in a fat depot-specific manner and could be associated with parameters of obesity, insulin resistance, and glucose metabolism...

..We have recently shown that vaspin mRNA expression in adipose tissue is related to parameters of obesity and glucose metabolism. However, the regulation of vaspin serum concentrations in human obesity and type 2 diabetes is unknown...

..We aimed to study circulating pigment epithelium-derived factor (PEDF) in vivo in association with insulin resistance and in vitro in human adipocytes...

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..This study investigates whether constitutive overexpression of PEDF inhibits the growth and hepatic micrometastasis of ocular melanoma...

..These findings indicate that cytosine methylation is important in the establishment and maintenance of cell type restricted gene expression...

..These paradoxical results may offer new insights regarding the role of maspin in ovarian cancer progression that may also impact diagnosis and treatment strategies...

..PEDF therefore might be a promising novel therapeutic agent for treatment of patients with melanoma...

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..Collectively, these data suggest that selective targeting of IL-6TS might allow to refine the currently available experimental anti-IL-6 therapies against PC...

..Polymers of serpins can also form in extracellular tissues where they activate inflammatory cascades...

..Furthermore, PEDF may represent a superior therapeutic approach to sepsis-associated hypotension, nephrotic syndrome, and other sight-threatening and life-threatening diseases resulting from excessive vascular permeability...

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..Analysis of human breast cancer specimens revealed that loss of maspin expression occurred most frequently in advanced cancers. These results support the hypothesis that maspin functions as a tumor suppressor...

..These results suggest that PEDF may be of therapeutic use, especially in retinopathies where pathological neovascularization compromises vision and leads to blindness...

..Our data demonstrate that Serpin-27A is required to restrict the phenoloxidase activity to the site of injury or infection, preventing the insect from excessive melanization...

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..These findings suggest that PEDF is a novel endogenous anti-inflammatory factor in the eye. The decrease of ocular PEDF levels may contribute to inflammation and vascular leakage in DR...

..We used ATGL(-/-) mice to determine the role of PEDF in regulating lipid and glucose metabolism...

..Taken together, these data suggest that neuroserpin is likely to be a critical regulator of tPA activity in the central nervous system, and as such may play an important role in neuronal plasticity and/or maintenance...

..Thus, we postulate that neuroserpin could represent a regulatory element of extracellular proteolytic events in the nervous system mediated by plasminogen activators or plasmin...

b>Serpins (serine protease inhibitors) are known as a diverse family of protease inhibitors; however, various other biological activities including tumor suppression, have been recently reported for these molecules...

..Thus, neuroserpin might function as an axonally secreted regulator of the local extracellular proteolysis involved in the reorganization of the synaptic connectivity during development and synapse plasticity in the adult...

..Our present study suggests that substitution of PEDF may be a novel therapeutic strategy for restenosis after balloon angioplasty...

..The molecular basis for this delicate control of endothelial cells is beginning to be understood and strategies to test the ability of PEDF to ameliorate or prevent vessel damage in the eye are developing rapidly...

..To investigate the roles of protease inhibitors in regulating this pathway, we cloned cDNAs for two new serpins (serpin-4 and serpin-5) from the tobacco hornworm, Manduca sexta...

..Visceral adipose tissue-derived serine protease inhibitor (vaspin) is a novel adipokine with insulin-sensitizing effects. However, the physiological role for vaspin in human metabolic regulation remains to be established...

..activation pathways carried out by different modules of serine proteases and their specific inhibitors serpins. Immune melanization proteases (IMP-1 and IMP-2) and Serpin-1 mediate hemolymph prophenoloxidase cleavage and ..

..These direct and indirect effects of PEDF have been examined in vitro and in vivo for a range of malignancies...

..As a potent inhibitor of tumor angiogenesis, pigment epithelium-derived factor (PEDF) has recently been studied and used as an anticancer agent in several tumor models...

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b>Serpins are a broadly distributed family of protease inhibitors that use a conformational change to inhibit target enzymes. They are central in controlling many important proteolytic cascades, including the mammalian coagulation pathways...

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..in these processes are regulated by feedback loops, local cofactor molecules, and serine protease inhibitors (serpins)...

..Our results map active regions for the two PEDF functions, signaling via distinct receptors, identify candidate peptides, and provide their mechanism of action for future development of PEDF-based tumor therapies...

..We propose that tumour-infiltrating RANKL-expressing cells lead to nuclear IKKalpha activation and inhibition of Maspin transcription, thereby promoting the metastatic phenotype...

b>Serpins compose the largest superfamily of peptidase inhibitors and are well known as regulators of hemostasis and thrombolysis...

..Vaspin is an adipokine with insulin-sensitizing effects identified from visceral adipose tissues of genetically obese rats...

..Consequently, vaspin could play inhibitory roles on inflammatory states of vascular SMCs...

..Ex vivo regulation of adipose tissue vaspin and the effects of metformin treatment on circulating vaspin levels in PCOS subjects were also studied...

b>Serpins are unique among the various types of active site proteinase inhibitors because they covalently trap their targets by undergoing an irreversible conformational rearrangement...

..Reduction of serum PEDF concentration associated with the development of chronic liver diseases may contribute to the progression of HCC. In addition, gene therapy using PEDF may provide an efficient treatment for HCC...

..Because hypoxia and VEGF regulate matrix metalloproteinases (MMPs), their effects on PEDF proteolysis were explored...

..The purpose of this study was to investigate whether PEDF gene is a potent tumor suppressor and a potential candidate for cancer gene therapy...

..The decrease in PEDF levels in the retina is at least partially responsible for the increase in VEGF expression and subsequent vascular leakage and neovascularization in diabetes...

..These results suggest that MSCs contribute to CNV and could serve as delivery vehicles of antiangiogenic agents for the treatment of a range of CNV-associated diseases...

..Our present study suggests that substitution of PEDF proteins may be a promising strategy in treatment of patients with early diabetic retinopathy...

..Altogether our data indicate that PEDF belongs to the subgroup of noninhibitory serpins and that its N-terminal region confers a neurite-promoting activity to the protein...

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..At present, no information is available on its expression in IPF...

..001) and with waist circumference in controls (p=0.015). In conclusion, serum vaspin levels are elevated in PCOS but neither a small weight loss nor metformin affect vaspin levels significantly...

..On the other hand, Mch4 could be a second upstream protease that is responsible for activation of the same protease cascade in CrmA-insensitive apoptotic pathways...

..35 [1.59; 3.46] versus AT/TT). This association appears to be independent of obesity. Our finding corroborates previous studies that suggested a link between the novel adipokine vaspin and glucose metabolism...

..Although serpins have been identified in isolated members of archea, bacteria, and plants, a remarkable expansion is found in ..

..This study provides in vivo evidence for a role of SERPIN B3 in inhibiting inflammation and favoring epithelial proliferation with increased TGF-β secretion and thus the likelihood of consequent fibrogenesis...

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..The aim of this study was to assess the vaspin and adiponectin concentrations on markers of insulin sensitivity and obesity in pubertal obese children and adolescents...

..Our data provide a basis for stemness regulation in vascular niches and indicate that Notch and PEDF cooperate to regulate self-renewal...

..In conclusion, transgenic mice expressing SCCA1 showed higher liver regenerative potential compared to wild-type mice, supporting the dual role of this serpin as an anti-apoptotic and pro-proliferative stimulus for liver cells in vivo...

..Most serpins are secreted and attain physiologic concentrations in the blood and extracellular fluids...

..Taken together, these results implicate an important role for endogenous KS in protection against salt-induced renal and cardiovascular injury in rats by suppressing oxidative stress, inflammation, hypertrophy, and fibrosis...

..We provide insight into the immense therapeutic potential of Maspin and the challenges related to its successful clinical translation...

..Therefore, P176S (C526T) substitution of maspin may result in a partial loss of the tumor suppressor function of this protein, contributing to decreased susceptibility to apoptosis and malignant progression...

..These results suggest that SERPINA3K is a high-affinity, endogenous antagonist of LRP6. The blockade of Wnt signaling may represent a unifying mechanism for the anti-inflammatory and anti-angiogenic effects of SERPINA3K...

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..Kinetic analysis of PAP-serpin-3 association strongly suggests that serpin-3 is a physiological regulator of the pro-PO activation reaction...

..11 in patients with neovascular AMD should be performed...

..The present study for the first time revealed that vaspin inhibits PDGF-BB-induced SMCs migration through inhibiting p38/HSP27 signals via preventing the ROS generation...

..Interestingly, activated matriptase-3 formed stable inhibitor complexes with an array of serpins, including plasminogen activator inhibitor-1, protein C inhibitor, alpha1-proteinase inhibitor, alpha2-..

..To investigate whether nuclear and cytoplasmic Maspin expression is associated with distinct clinicopathological parameters and TP53 expression in a representative series of primary non-small cell lung cancer (NSCLC)...

..Additional studies are needed to evaluate further this expression profile of maspin in breast cancer...

..The aim of this study was to investigate the regulation and autocrine function of PEDF in human adipocytes and to determine its paracrine effects on human skeletal muscle cells (hSkMC) and human smooth muscle cells (hSMC)...

..SCCA) 1 and 2 are tandemly arrayed genes that encode two high-molecular-weight serine proteinase inhibitors (serpins)...

..Our objective was to evaluate the impact of acute weight loss and metabolic changes on serum vaspin concentrations in morbidly obese subjects following laparoscopic Roux-en-Y gastric bypass (RYGB) surgery...

..Visceral adipose tissue-derived serine protease inhibitor (vaspin) has been suggested as a novel adipocytokine related to obesity and insulin sensitivity in adults...

..b>Serpins have been shown in many animals to be key regulators of innate immune reactions...

..Furthermore, our results support a current hypothesis that maspin blocks tumor invasion and motility by inhibiting localized pericellular proteolysis...

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..In conclusion, chronically damaged hepatocytes produce SERPINB3 and TGF-beta, and the anti-protease activity of this serpin might be implicated in TGF-beta1 induction...

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..We also discuss the prospects for PEDF therapy and the need for a closer evaluation of issues such as delivery, stability and potential toxicity...

..This study investigated the effects of pigment epithelium-derived factor (PEDF) on advanced glycation end-product (AGE)-induced cytotoxicity in porcine retinal pericytes and the signalling mechanism involved...

..Some may inhibit fungal or bacterial proteinases. Others probably have roles in regulating endogenous proteinases involved in coagulation, prophenol oxidase activation, or cytokine activation...

..Thus, SCCA2 overexpression in squamous tumor cells contributed to their survival by protecting them against TNF-alpha-induced apoptosis...

Serine proteinase inhibitors (Serpins) are irreversible suicide inhibitors of proteases that regulate diverse physiological processes such as coagulation, fibrinolysis, complement activation, angiogenesis, apoptosis, inflammation, ..

..These findings seminally indicate that PEDF may have potential as an anti-cancer agent against chondrosarcoma...

..These viral countermeasures to host defenses against infection may contribute significantly to the pathology associated with poxvirus infections...

..These results suggest that maspin production in myoepithelial cells could downregulate the malignant phenotype of breast cancer...

b>Serpins are known to be necessary for the regulation of several serine protease cascades...

..The purpose of this study was to determine the effect of polarization of hES-RPE monolayers on their ability to promote survival of RPCs...

..These findings show that neuroprotective gene therapy using hPEDF can protect against retinal ganglion cell death, and support the potential feasibility of neuroprotective therapy for intractable glaucoma...

..Two innovative therapeutic approaches, based upon the infusion of serpins, one derived from a myxoma virus, Serp-1, and one mammalian serpin, neuroserpin (NSP), have been investigated in ..

..Extensive searches within the largest family of peptidase inhibitors, the serpins (e.g., antithrombin and [unreadable]1-antitrypsin), failed to yield candidate regulatory genes...

..and validation of Amblyomma americanum and Ixodes scapularis tick saliva serine protease inhibitors (serpins) as vaccine target antigens for immunization of white tailed deer against tick infestation...

..Plasminogen activator inhibitor-1 (PAI-1) is a member of the family of endogenous serine protease inhibitors (serpins) that controls the activation of plasminogen into plasmin by tissue and urokinase type plasminogen activators (..

..antitrypsin (A1AT) deficiency emphasizes the role of A1AT as an elastase inhibitor, serine protease inhibitors (Serpins), including A1 AT, have broader biological effects beyond their classical action as protease inhibitors...

..fXI, potentiating its activation by thrombin, fXII and autoactivation, and may down-regulate fXIa inhibition by serpins. In Aim 1, we will use an ex vivo flow model to study the importance of fXI and fXII to thrombus formation in ..

..Two serpins, anti-thrombin and protein Z-dependent protease inhibitor (ZPI), are known to inhibit procoagulant proteases in a ..

..by applicant): The proteolytic activity of coagulation proteases is regulated by the serine protease inhibitors (serpins) in plasma...

..3. Investigate the regulation of protease pathways in hemolymph by serpins, using in vitro, ex vivo, and in vivo experimental approaches...

..In humans, serpins are involved in regulation of important of proteolytic pathways that are essential to life such as blood ..

..We will focus on an important family of secreted proteins, the inhibitory serpins, which fold into native structures with high contact order...

..b>Serpins are involved in the regulation of many physiological processes including fibrinolysis, complement activation, ..

..Furthermore recent reports in the neuroscience literature applying cell culture models suggest that some serpins may be neuroprotective through inhibition of excitotoxicity...

..In proposed studies, we will determine the repertoire of serine proteinase inhibitors (serpins) expressed in normal and virally infected murine hepatocytes and determine the role of cytokines in regulating ..

..myeloproliferative drugs) may impart proliferative effects through S-glutathionylation of the protease inhibitor serpins. Mechanistically, these protein families are subject to redox regulation and have roles in regulation of marrow ..

..We will utilize this mouse and study inhibition of cCatL by a group of enzymes called serpins. Our initial focus will be on SERPINB13 (hurpin) which is classically located in the cytosol of skin cels and ..

..The M1 antigen, which bears sequence homology to some pox virus serpins (although it lacks critical catalytic residues) and to the ?HV68 secreted high affinity chemokine binding protein ..

..Serine protease inhibitors (serpins) are a family of proteins with high structural homology...

..in periodontal development and the periodontal ligament, 6) epithelial-connective tissue interactions and scar formation, 7) molecular mechanisms of serpins in oral cancer tumorgenesis, 8) molecular analysis of rhabdomyosarcoma.

..b>Serpins are conserved components of many organisms and have been implicated in a variety of cellular events including the ..

..There are endogenous inhibitors of proteases, including SERine Protease INhibitors (Serpins) and Stefin protease inhibitors, which are differentially upregulated with Alternaria exposure...

..There are endogenous inhibitors of proteases, including SERine Protease INhibitors (Serpins) and Stefin protease inhibitors. These inhibitors are strongly upregulated with Alternaria exposure...

..Ultimately, these studies will provide the basis for development of highly specific treatments for patients with necrosis-associated disorders. ..

..The working hypothesis in this aim is that application of CVLS to i) serpins (antithrombin and heparin cofactor II);ii) proteases (factors IIa, Xa and IXa of the coagulation cascade);and iii)..

..They focus here on poxvirus-encoded proteinase inhibitors (serpins). Orthopoxviruses, including cowpox virus (CPV), encode three serpins: SPI-1, SPI-2/crmA and SPI-3...

The long-term goal is to define the molecular mechanisms of thrombin (T) inhibition by the serpins, heparin cofactor II (HCII) and plasminogen activator inhibitor-1 (PAI-1), implicated in arterial thrombosis...

..We focus here on poxvirus- encoded serine proteinase inhibitors (serpins). Orthopoxviruses, including cowpox virus (CPV), encode three serpins: SPI-1, SPl-2/crmA and SPI-3...

..The objective of this research is to better understand the different mechanisms by which the serpins antithrombin (AT) and protein C inhibitor (PCI) inhibit free thrombin and thrombin bound to thrombomodulin (TM)...

Human plasma contains a superfamily of serine proteinase inhibitors, the serpins, which are glycoproteins of Mr = 40,000- 60,000...

..This places PN1, FXIa, APP and the LRP in a common biochemical pathway that may be directly involved in Alzheimer's disease pathology. ..

..to our understanding of the biochemical properties and biological functions of serine protease inhibitor (serpins) as well as provide me with a foundation for a career as an independent investigator in the molecular and ..

..Project 3 (S.C. bock, Serpin Structure and the Development of Neutrophil-Resistant Serpins) will focus on the structure-activity relationships with a naturally occurring anticoagulant serpin, antithrombin ..

..We are studying a family of high molecular weight plasma and cellular proteins, the serpins--serine protease inhibitors, some of which have evolved the remarkable property of inhibiting these proteases ..

..of proteins are known to be tyrosine sulfated in man, including certain adhesion molecules, coagulation factors, serpins, extracellular matrix proteins, and hormones and some of these require sulfation for optimal function...

..Lines of evidence suggest that serpins, namely AAT and elafin, may play important roles in protecting islets from autoimmunity and alloimmnunity...

..and distribution patterns of SCCA1 and SCCA2 in the airways, the investigators hypothesize that these two serpins protect the airways against proteinase mediated injury...

..Among the local proteinase inhibitors, members of the ov-serpin family (ovalbumin-related serpins) are an emerging group of proteins that are abundantly expressed by several cell types in the lung, including ..

DESCRIPTION (provided by applicant): Serine proteinase inhibitors (serpins) play a central role in a wide variety of physiologic processes involved in aging...

..agents and cardiovascular treatment; development of anti-sickling agents for sickle cell hemoglobin; serpins and their complexes with heparin and other ligands, which play critical roles in fibrinolysis, thrombosis and ..

..of this information and knowledge of protein conformational changes that occur during proteinase inhibition by serpins, a working model for the molecular mechanism underlying ATIII heparin cofactor activity has been proposed...

..biology contain tyrosine sulfate, including adhesion molecules, coagulation factors, complement components, serpins, and extracellular matrix proteins...

..those on the structure of the nature of the inhibition mechanism of both serine and cysteine proteinases and how serpins are able to kinetically trap complexes with proteinase (Project 2, Steven Olson, P.I...

..for the production of regulatory molecules, such as cytokines, serine pro-proteases and their inhibitors (serpins). Stable, dominant-negative and bloodmeal-activated, over-expressed Dorsal Aedes strains will be generated...

..Predominant in this are the serpins, members of an evolutionary related superfamily that are demonstrably responsible for regulating the ..

..type 2 (PAl-2) is structurally and functionally a member of a large family of serine protease inhibitors or serpins. Serpins are key regulators of important biological processes such as complement activation, fibrinolysis, ..

..Our central hypothesis is that Toxoplasma uses natural serine proteases (serpins) to control innate immune defenses including inflammation and complement fixation via the alternative pathway...

..chuPA manifests its activity in an uncontrolled, unregulated manner: It is insensitive to the known uPA-specific serpins, it accumulates in plasminogen-free cultures as active enzyme, and most unusually it is activated by an ..

..MMP structure, the enzyme has a unique substrate specificity, hydrolyzing certain serine protease inhibitors (serpins) including alpha1 anti-trypsin (alpha1 proteinase inhibitor, alpha1-PI)...

..The aims of this study are 1.) Enhance tumor selectivity and safety by combining deletions of vaccinia serpins with TK and VGF, and define the mechanism of tumor selective replication...

..FENIB shares a common molecular pathophysiology with other mutated serpins, i.e...

..b>Serpins are involved in the regulation of such diverse processes as coagulation, fibrinolysis, complement activation, ..

..to specifics of protease mechanisms (Ben Dunn, Chairman), 2 to serine protease inhibitors of the plasma (Serpins) (Robin Carrell, Chairman), one to effector modules of proteases (Frank Castellino, Chairman), one to protease ..

..expansion diseases and nonneurological diseases like liver disease that accompanies the misfolding of serpins. This conference will integrate discussions of advances in understanding the structural basis for misfolding and ..

..that proteins play in apoptosis, still another (Moyer) is looking to define the structure of poxvirus encoded serpins. (Hargrave) is looking to better understand the proteins that bind to rhodopsin and the role of adhesion related ..

..of thrombin formation through inhibition of upstream coagulation factor Xa;2) direct inhibition of thrombin by serpins antithrombin (AT) and heparin cofactor II (HCII);and, 3) attenuation of thrombin's procoagulant activity ..

..Kazal, and Bowman-Birk families make do with lock-and-key type interactions to inhibit target proteinases, serpins have now been shown by x-ray crystallography, NMR spectroscopy and FRET to employ a remarkable conformational ..

..For antithrombins that have been activated by mutation,[unreadable] x-ray crystallography, through collaboration with Dr. Robin Carrell,[unreadable] will be used.[unreadable]..

..As part of the facility, a resource will be established for development of procedures for intein-based segmental isotopic labeling of proteins, as well as for production of segmentally labeled DNA and RNA species. ..

..Olson, with interests in serpin inhibition mechanism, Dr. Patston, with interests in the structure of the serpin angiotensinogen, and Dr. Silver, who is characterizing a unique silver binding protein, silE. ..

Partial support is requested for the 3rd International Symposium on the biology, structure, and function of serpins, to be held in Chicago, Illinois June 2-5, 2002...

..presence of calcium, (vi) heparin binding to antithrombin variants, (vii) interaction of antithrombin and other serpins with target proteinases, (viii) stability of native and cleaved serpins, (viii) binding of hormone to thyroxine ..

..The knowledge gained will be invaluable for design of therapeutics against such infections or in amelioration of diseases associated with aberrant functioning of processes such as blood coagulation. [unreadable] [unreadable] [unreadable]..

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