1978 — 1980 |
Lavail, Jennifer (co-PI) [⬀] Glass, Laurel Rosen, Steven Calarco, Patricia |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Purchase of a Liquid Scintillation Counter & Ultracentrifuge @ University of California-San Francisco |
0.915 |
1983 — 1985 |
Rosen, Steven |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Molecular Mechanisms of Intercellular Adhesion in the Cellular Slime Molds and Lymphocytes @ University of California-San Francisco |
0.915 |
1985 — 2009 |
Rosen, Steven D |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Cell Surface Lectins and Intercellular Adhesion @ University of California San Francisco
The movement of lymphocytes from the blood into secondary lymphoid organs and back to the blood again is known as lymphocyte recirculation. This process is an important component of immune surveillance, as it facilitates the exposure of the body's repertoire of lymphocyte specificities to sequestered and processed antigens in the lymphoid organs. In certain diseases the migration of lymphocytes into inappropriate compartments (i.e, joint synovia during rheumatoid arthritis) leads to tissue damage. The overall objective of our research is to understand the biochemical mechanisms involved in the attachment of blood- borne lymphocytes to specialized high endothelial venules (HEV) found in secondary lymphoid organs. This highly specific cell-cell recognition event, which is dependent on both lymphocyte type and the anatomic site of the HEV, initiates the extravasation of normal lymphocytes from the blood into the parenchyma of lymphoid organs and may also determine the dissemination sites of lymphoid malignancies. Our previous work has established that lymphocytes express a cell surface carbohydrate-binding receptor (CBR) that participate in the attachment of lymphocyte to HEV in peripheral lymph nodes (i.e., "lymphocyte homing receptor"). Also we established that the lymphocyte attachment sites on PN HEV require sialic acid for their activity. The major objectives of our proposed research are: 1) to determine the relationship between the CBR and the MEL-14 antigen, a 80 kDa glycoprotein previously implicated in lymphocyte homing; 2) to determine the relationship between a soluble lymph factor with specific HEV- binding activity and the CBR; 3) to identify the linkage of sialic acid required for the activity of PN HEV attachment sites; 4) to identify the actual attachment sites for lymphocytes on PN HEV and PP HEV; and 5) to identify the homing receptor that mediates attachment of lymphocytes to HEV in Peyer's patches, a gutassociated lymphoid organ.
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1987 — 1988 |
Rosen, Steven D |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cell Surface Lectins &Intercellular Adhesion @ University of California San Francisco
The movement of lymphocytes from the blood into secondary lymphoid organs and back to the blood again is known as lymphocyte recirculation. This process is an important component of immune surveillance, as it facilitates the exposure of the body's repertoire of lymphocyte specificities to sequestered and processed antigens in the lymphoid organs. In certain diseases the migration of lymphocytes into inappropriate compartments (i.e, joint synovia during rheumatoid arthritis) leads to tissue damage. The overall objective of our research is to understand the biochemical mechanisms involved in the attachment of blood- borne lymphocytes to specialized high endothelial venules (HEV) found in secondary lymphoid organs. This highly specific cell-cell recognition event, which is dependent on both lymphocyte type and the anatomic site of the HEV, initiates the extravasation of normal lymphocytes from the blood into the parenchyma of lymphoid organs and may also determine the dissemination sites of lymphoid malignancies. Our previous work has established that lymphocytes express a cell surface carbohydrate-binding receptor (CBR) that participate in the attachment of lymphocyte to HEV in peripheral lymph nodes (i.e., "lymphocyte homing receptor"). Also we established that the lymphocyte attachment sites on PN HEV require sialic acid for their activity. The major objectives of our proposed research are: 1) to determine the relationship between the CBR and the MEL-14 antigen, a 80 kDa glycoprotein previously implicated in lymphocyte homing; 2) to determine the relationship between a soluble lymph factor with specific HEV- binding activity and the CBR; 3) to identify the linkage of sialic acid required for the activity of PN HEV attachment sites; 4) to identify the actual attachment sites for lymphocytes on PN HEV and PP HEV; and 5) to identify the homing receptor that mediates attachment of lymphocytes to HEV in Peyer's patches, a gutassociated lymphoid organ.
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1993 |
Rosen, Steven D |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cell Surface Lectins and Intercelluar Adhesion @ University of California San Francisco
The movement of lymphocytes from the blood into secondary lymphoid organs, such as lymph nodes, and back to the blood again is known as lymphocyte recirculation. This process is an essential component of immune surveillance, as it maximizes the exposure of the body's repertoire of lymphocyte specificities to antigens that become sequestered and processed within secondary lymphoid organs. A primary step in the migration of blood-borne lymphocytes into a lymphoid organ is their highly specific adhesion to the specialized endothelial lining of postcapillary venules known as high endothelial venules or HEV. Lymphocyte adherence to HEV in lymph nodes is mediated by a lymphocyte surface molecule known as gp90MEL, which was initially identified in the mouse by an adhesion blocking monoclonal antibody, MEL-14. As revealed by its cloning, gp90MEL is a type I transmembrane protein consisting of calcium-dependent lectin domain, an EGF-like domains, two complement-regulatory domains, a transmembrane domain, and a short cytoplasmic tail. gp90MEL, now commonly referred to as LECAM-1, is a member of the newly emerging "selectin" or "LECAM" family of cell-cell adhesion proteins, which also includes ELAM-1 and GMP-140/PADGEM. As a consequence of their amino-terminal lectin domains, all of these proteins function as calcium-dependent lectins. Moreover, all recognize sialylated ligands. In the case of LECAM-1, biological ligands from lymph node HEV have been identified as two sulfated, sialylated, and fucosylated O-linked glycoproteins, known as Sgp50 and Sgp90. The focus of the present grant proposal is the biochemical and functional characterization of these ligand molecules. The specific aims are as follows: 1) using a soluble recombinant form of LECAM-1 as the basis for an affinity matrix, to isolate chemical quantities of the ligands from bovine lymph nodes; 2) with polyclonal and monoclonal antibodies prepared against the ligands, to confirm that the ligands are localized to lymph node HEV and serve as adhesion sites for lymphocytes; 3) to determine whether one or both of the ligand molecules can be reconstituted as adhesion molecules on a plastic substratum; 4) in collaboration with Genentech, to clone the polypeptides of the ligand molecules; 5) at the biochemical and molecular levels, to study the biosynthesis and cytokine regulation of the ligand molecule in a cell culture system of HEV endothelial cells; 6) to determine by metabolic radiolabeling techniques, the carbohydrate structures of the ligand oligosaccharides and to define the minimal carbohydrate recognition determinants of these carbohydrates; and 7) based on the knowledge that LECAM-1 on neutrophils mediates the rolling interaction of neutrophils with postcapillary venules at inflammatory sites, to identify the venular ligand for LECAM-1 and to compare them structurally to the HEV-ligands. From these studies a detailed biochemical understanding is likely to emerge of a critical cell adhesion event which is important not only in the normal trafficking of lymphocytes in the body but also in the targeting of leukocytes to inflammatory sites.
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1994 — 1996 |
Rosen, Steven D |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
L-Selectin in Leukocyte Myelin Interactions @ University of California San Francisco
Multiple sclerosis is the principle CNS demyelinating disease in humans. It is characterized by clearly demarcated plaques of myelin damage in association with inflammatory cell infiltrates. Work with models of experimental allergic encephalomyelitis (EAE) indicate that the induction of the disease involves class II restricted CD4+ T cells with specificity for defined epitopes of myelin basic protein or other neuroantigens. However, recent evidence indicates that while these neuroantigen-specific lymphocytes can orchestrate the influx of a large number of inflammatory cells into the CNS, the actual demyelination process depends on the action of inflammatory cells without apparent immune reactivity to neuroantigens. Our work addresses a potential mechanism by which these nonspecific cells interact with myelin. Our previous studies raise the possibility of a primary role for the lectin-like leukocyte receptor called L-selectin. Using antibodies and specific carbohydrates as inhibitors of L-selectin and employing a soluble recombinant form of L-selectin to identify ligand sites, we have shown that L-selectin can mediate the in vitro binding of lymphocytes to myelinated tracts of the CNS. In the present application, we plan to investigate the pathologic significance of what is most likely a fortuitous interaction between L-selectin and carbohydrate-bearing ligands within myelin membranes. Specifically, we will ask: l) Does L- selectin on leukocytes cause the targeting of the these cells to myelin? and 2) Does myelin damage then ensue from a process of cell-mediated toxicity or from the local release of cytokines such as TNF-alpha and lymphotoxin? Our planned experiments will consider whether blockade of L- selectin by antibodies will be sufficient to prevent or reduce clinical signs and demyelination in chronic relapsing models of EAE and whether a L-selectin knockout mouse is not susceptible to the passive transfer of the disease. Secondly, we will investigate whether signaling can occur through ligation of cell surface L-selectin and whether leukocyte adherence to myelin via L-selectin can trigger signaling. A final objective is to identify and characterize the myelin-associated ligand for L-selectin. Our experiments will investigate a novel mechanism by which CNS demyelination may occur. Our results may have broad significance for devising new therapies for intervention in a variety of CNS demyelinating conditions.
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1996 — 2002 |
Rosen, Steven D |
P41Activity Code Description: Undocumented code - click on the grant title for more information. |
Synthesis of Carbohydrate Ligands For Adhesion Molecule L Selectin @ University of California San Francisco
Note: There is a continution page for this abstract in Microwoft Word, and there are figures to be pasted in. Introduction. The selectins are a family of three adhesion molecules (L-, E- and P-selectin) thatare involved in the initial attachment of blood-borne leukocytes to endothelial cells during the process of emigration from the bloodstream into the surrounding tissue. All three selectins bindto carbohydrate-based ligands on opposing cells in a calcium-dependent manner. L-selectin is unique among the selectins by virtue of its constitutive expression on all classes of circulating leukocytes. In addition, L-selectin plays a key role in leukocyte recruitment during a number of acute and chronic inflammatory conditions, focusing a tremendous amount of interest on the nature of the carbohydrate ligands on opposing endothelial cells. We have initiated a program aimed at the structural identification of carbohydrate ligands for L-selectin. Our approach involves analysis of the oligosaccharide structures on biological selectin ligands and the chemical synthesis of identified structures to directly demonstrate functional activity. Mass spectrometry is central to the characterization of our synthetic products, and will be the principal analytical tool in the direct structural identification of the carbohydrate epitopes on biological L-selectin ligands. Results and Discussion. Previous work in this laboratory has led to the molecular identification of two biological glycoprotein ligands for L-selectin, termed GlyCAM-1 and CD34. The oligosaccharides on these glycoproteins are sulfated and sialylated, two modifications which were shown to be essential for L-selectin recognition. Preliminary characterization of the oligosaccharides on GlyCAM-1 using metabolic radiolabeling techniques has revelealed the presence of a novel capping group, 6'-sulfo sialyl Lewis x [NeuAca2,3(SO4-6)Galb1,4(Fuca1,3)GlcNAc, 1]. Thus, it is hypothesized that sulfation of the sialyl Lewis x tetrasaccharide on the 6'-position imparts high affinity binding activity to L-selectin. To test this hypothesis, we have designed a chemical/enzymatic synthesis for sulfated oligosaccharides related to structure 1. Our first target is compound 6 (scheme 1), in which the sialic acid residue of structure 1 has been replaced with a synthetically more accessible sulfate ester. The synthetic route begins with selective protection of the readily available disaccharide lactose (2) to afford derivative 3 in three steps. The 3'-, 4'- and 6'-positions are then selectively liberated with acid to afford compound 4. Chemical sulfation proceeds selectively at the 3'- and 6'-positions yielding, after deprotection, disulfated intermediate 5. The structures of intermediates 2-5 have been assigned in part using mass spectrometry. Finally, enzymatic fucosylation using a recombinant fucosyltransferase (FucT V) and GDP-fucose will afford target moledule 6. Currently, we have completed the synthesis of 5 and tested this intermediate for L-selectin binding activity. Preliminary results indicate that compound 5 binds to L-selectin more potently thansimilar derivatives lacking the sulfate ester at the 6'-position. Thus, this key sulfate ester appears to contribute significantly to L-selecting binding activity. We anticipate that synthetic oligosaccharides such as compound 6 will be even more potent as L-selectin antagonists, and may demonstrate anti-inflammatory activity in vivo. Finally, we plan to complement our metabolic radiolabeling analysis of the GlyCAM-1 oligosaccharides with direct characterizat ion by mass spectrometry.
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1996 — 2005 |
Rosen, Steven D |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Role of Selectins in Leukocyte Recruitment to Inflamed Airways in Asthma @ University of California San Francisco
selectins; leukocyte activation /transformation; asthma; eosinophil; inflammation; receptor binding; respiratory hypersensitivity; cell migration; integrins; chemoattractants; immunologic assay /test; human subject; laboratory mouse;
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1999 — 2002 |
Rosen, Steven D |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sulfotransferase in the Synthesis of L-Selectin Ligands @ University of California San Francisco
L-selectin mediates the initial adhesion of lymphocytes to high endothelial venules (HEV) in lymph nodes during the process of lymphocyte recirculation. It also functions in leukocyte-leukocyte and leukocyte-endothelial interactions that occur during trafficking of leukocytes into inflammatory sites in both acute and chronic settings. L-selectin functions as a lectin-like receptor in recognizing a discrete set of HEV-ligands including GlyCAM-1, CD34, podocalyxin, Sgp200 and MAdCAM-1. These ligands are sulfated, fucosylated and sialylated, and all three of these modifications are required for optimal recognition by L-selectin. In addition, these glycoproteins are recognized by the monoclonal antibodies (MECA 79 and G72), which bind to sulfated substructures that are essential for their ligand activity. A detailed carbohydrate analysis of GlyCAM-1 has revealed that specific sulfation modifications of sialyl Lewis X are found: Gal-6-sulfation and N- acetylglucosamine-6-sulfation. This proposal is directed at the identification of the sulfotransferases, which catalyze these specific sulfation modifications of the HEV-associated ligands. One of the few cloned sulfotransferases that modifies carbohydrate chains is the chick chondroitin 6/keratan sulfate sulfotransferase (C6ST/KSST). This enzyme is capable of catalyzing the addition of sulfate to the 6-position of Gal in simple acceptor structures. We gave recently cloned 3 human cDNAs (GST 1, 2, and 3) which are highly homologous to the chicken C6ST/KSST. One of these (GST 3) is selectively expressed in the endothelial cells of HEV. The specific aims of the present proposal are: 1)To determine whether expressed proteins corresponding to the newly cloned GSTs (especially GST 3) catalyze the appropriate addition of sulfate moieties to model carbohydrate acceptors and to the carbohydrate chains of GlyCAM-1; 2) To identify the sulfated carbohydrate epitope recognized by MECA 79; and 3) To obtain cDNAs encoding HEC sulfotransferases by expression cloning techniques using the sulfation-dependent mAbs (G72 and MECA 79) and L-selectin. Understanding these enzymes has important biomedical implications, because the regulation of these enzymes provides a potential mechanism to control the expression of functional ligands for L-selectin, and thereby to control leukocyte trafficking into lymphoid organs and inflammatory sites.
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2003 — 2007 |
Rosen, Steven D |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sulfotransferases in the Synthesis On L-Selectin Ligands @ University of California San Francisco
L-selectin mediates the initial adhesion of lymphocytes to high endothelial venules (HEV) in lymph nodes during the process of lymphocyte homing. It also functions in leukocyte-endothelial interactions underlying the trafficking of leukocytes into chronic inflammatory sites. L-selectin functions as a lectin-like receptor by recognizing a discrete set of HEV-expressed ligands including GlyCAM-1, CD34, and podocalyxin. These ligands bear O-linked carbohydrate chains that are sulfated, fucosylated and sialylated. All three of these modifications are required for optimal recognition by L-selectin. A detailed analysis of GlyCAM- 1 and CD34 has revealed that tile recognition determinant for L-selectin binding is a sulfated structure known as 6- sulfo sLex, a tetrasaccharide that possesses a sulfate ester on the C-6 position of N-acetylglucosamine. In the search for the sulfotransferase that elaborates this critical modification within HEV, the Rosen laboratory has cloned a family of GlcNAc-6-O-sulfotransferases. Two of these, known as GST-2 and GST-3, are present in HEV. GST-3 has been given the name HEC-GlcNAc6ST because of its highly restricted expression in high endothelial cells (HEC) of HEV. The direct involvement of HEC-GlcNAc6ST in elaborating L-selectin ligands has been established by disrupting this gene in mice. HEC-GIcNAc6ST knockout mice exhibit a significant but incomplete loss of HEV-expressed ligands for L-selectin and an impairment of lymphocyte homing to lymph nodes. The present grant will continue the study of HEC-GlcNAc6ST and the related enzyme, GST-2, with respect to their functions in lymphocyte homing and inflammatory leukocyte trafficking. The specific aims are: 1) To determine the contribution of HEC-GIcNAc6ST to the activity of L- selectin ligands generated in situ; 2) To determine the expression of HEC-GlcNAc6ST in activated endothelium at sites of inflammation; 3) To determine the contribution of HEC-GlcNAc6ST to leukocyte recruitment and disease in mouse models of chronic inflammation; and 4) To determine the contribution of GST-2 to the generation of L-selectin ligands. Gaining further understanding of these sulfotransferases has considerable biomedical relevance, because these enzymes are potential therapeutic targets for blocking inflammatory diseases.
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2006 — 2007 |
Rosen, Steven D |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Role of Heparan Sulfate-Degrading Sulfatases in Pancreatic Adenocarcinomas @ University of California San Francisco
[unreadable] DESCRIPTION (provided by applicant): Pancreatic adenocarcinoma is one of the most deadly malignancies in human for which there are very limited treatment options. There is great interest in the possible role of embryonic signaling pathways in the initiation and progression of this cancer and others. Among these pathways is canonical Wnt signaling, which is involved in the proliferation and self-renewal of stem/progenitor cells and has been speculated to have a similar role in cancer stem cells. The presence of activated beta-catenin in pancreatic tumor samples suggests that 30-40% of these tumors manifest Wnt signaling. Moreover, Matthias Hebrok and colleagues at UCSF have discovered that active Wnt signaling is required for the growth of several pancreatic adenocarcinoma cell lines in vitro. Our exploratory R21 project proposes to investigate the role of two novel sulfatases, called HSulf-1 and HSulf-2, in Wnt signaling within pancreatic adenocarcinomas and their contributions to the growth and tumorigenicity of these cancer cells. The Sulfs are extracellular enzymes which act on heparan sulfate proteoglycans (HSPGs) to remove a specific sulfation modification (glucosamine-6-O-sulfation). One known biological activity of the Sulfs is to modulate the interaction of Wnt ligands with HSPGs and to potentiate the ability of the Wnts to activate their signal transduction receptors. Our preliminary studies have found the expression of SULF1 or SULF2 transcripts in 23 of 24 pancreatic adenocarcinoma cell lines and the presence of Sulf-1 or Sulf-2 protein in 4/4 of these cell lines and 3/5 of pancreatic tumor samples. Expression of a dominant negative form (enzymatically-inactive mutant) of either Sulf-1 or Sulf-2 in 3 out of 4 of these lines resulted a reduction in Wnt signaling. Furthermore, co-culturing the same three cell lines in the presence of inactive Sulf protein produced a parallel reduction in Wnt signaling and cell growth in vitro. The proposed research will employ lentivirus-transduced shRNA expression to silence one or both Sulfs in representative pancreatic adenocarcinoma cell lines. Our Aims are: 1) To determine the effects of Sulf silencing on the growth and Wnt signaling of these cells in vitro; and 2) To determine the effects of Sulf silencing on the ability of the cells to form tumors in nude mice. Positive results from these studies should stimulate considerable interest in the Sulfs as possible targets (for small molecules or function-blocking antibodies) for the treatment of pancreatic adenocarcinoma in humans. [unreadable] [unreadable] [unreadable]
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2007 — 2010 |
Rosen, Steven D |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sulfotransferases in the Synthesis of L-Selectin Ligands @ University of California San Francisco
[unreadable] DESCRIPTION (provided by applicant): Lymphocytes home from the blood into lymph nodes during the process of lymphocyte recirculation. Homing is initiated by the rolling of lymphocytes on high endothelial venules (HEVs) within the lymph node. This step is mediated by L-selectin, a C-type lectin, which recognizes a set of carbohydrate-based ligands on HEVs. A function-blocking mAb called MECA-79 recognizes the same complex, referred to as PNAd. The ligands are sialomucins modified by GlcNAc-6-sulfate, sialyl Lewis x, and Gal-6-sulfate. We have studied double knockout (DKO) mice in which two GlcNAc-6-O-sulfotransferases that are present in HEVs have been inactivated. These mice exhibit a 75% reduction in homing to lymph nodes and the total elimination of PNAd (complete loss of MECA-79 staining) from HEVs. We will investigate the possibility that Gal-6-sulfate modifications contribute to the "residual" ligand activity on HEVs in DKO mice, as well in mice in which GlcNAc-6-O-sulfotransferases are intact (Aim 1). PNAd+ blood vessels, which co-express GlcNAc-6-O-sulfotransferase, are present in joint tissues of rheumatoid arthritis (RA) patients. This finding is recapitulated in three mechanistically-distinct models of inflammatory arthritis in mouse. We have characterized a new antibody, called Clone 40, with very similar binding properties as MECA-79 but more suitable for use in animal studies. We will employ the DKO mice, together with Clone 40, in the mouse models of arthritis to study the role of the sulfotransferases and their sulfated products in disease pathogenesis (Aim 2). Since some murine models have been very predictive of efficacious human therapeutics (e.g., anti TNF-1 therapy), our work may lead to new approaches for the treatment of RA. We will also investigate a sheep model of asthma in which L-selectin appears to play a highly novel role (Aim 3). Our experiments suggest that extravasated leukocytes in the airways can utilize L-selectin to react with sulfated mucin ligands, which are expressed in inflamed airways. This interaction leads to activation of the leukocytes, which results in an increase in airway resistance and airway responsiveness, two hallmarks of asthma. To evaluate this hypothesis, we will determine whether isolated airway mucins can activate neutrophils through binding to L-selectin and cause the secretion of broncho-active substances. Finally, we have discovered that airway mucins in lungs are ligands for Siglec-8, a receptor known to bind sulfated and sialylated sugars. This Siglec is present on eosinophils and can induce apoptosis when artificially cross-linked by antibodies. We will determine whether these mucins are natural ligands for Siglec-8, serving to crosslink Siglec-8 on eosinophils and thus triggering apoptosis of these leukocytes (Aim 4). This would provide a homeostatic control mechanism for removing eosinophils that accumulate in allergic diseases, such as in asthmatic airways. Understanding this mechanism may lead to new pharmacologic approaches for dampening eosinophil responses. [unreadable] [unreadable] [unreadable]
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2008 — 2012 |
Rosen, Steven D |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Sulfs and Injury Repair in Mucosal Epithelia @ University of California San Francisco
2-Amino-2-Deoxyglucose; 3-D; 3-Dimensional; A549; Acute Pulmonary Injury; Adherent Culture; Adhesins, Bacterial; Agonist; Alveolar; Alveolar Cell; Alveolar wall; Antibodies; Bacterial Adhesins; Binding; Binding (Molecular Function); Body Tissues; Cancers; Catabolism; Cell Communication and Signaling; Cell Growth in Number; Cell Line; Cell Lines, Strains; Cell Locomotion; Cell Migration; Cell Movement; Cell Multiplication; Cell Proliferation; Cell Signaling; Cell surface; Cell-Extracellular Matrix; CellLine; Cells; Cellular Expansion; Cellular Growth; Cellular Migration; Cellular Proliferation; Collaborations; Complement; Complement Proteins; Cornea; Cultured Cells; Culturing, in vitro Organ; Culturing, in vitro Vertebrate, Organ; Cyst; Cytokines, Chemotactic; D-Glucose, 2-amino-2-deoxy-; Development; Distal; ECM; Enzyme Activation; Enzymes; Epithelial; Epithelial Cells; Epithelium; Epithelium, Anterior Corneal; Epithelium, Corneal; Event; Extracellular Matrix; Eye; Eyeball; GAG; GAG Gene; GFAC; Gene Targeting; Glucosamine; Growth Agents; Growth Factor; Growth Factors, Proteins; Growth Substances; HSPG; Heparan Sulfate Proteoglycan; Homologous Chemotactic Cytokines; Human; Human, General; Image; In Vitro; Infection; Inflammatory; Injury; Intercrines; Intracellular Communication and Signaling; Knockout Mice; Ligand Binding; Ligands; Lung; Lung Alveolar Epithelia; Lung Injury, Acute; MMPs; Malignant Neoplasms; Malignant Pancreatic Neoplasm; Malignant Tumor; Malignant neoplasm of pancreas; Mammals, Mice; Man (Taxonomy); Man, Modern; Matrix Metalloproteinases; Metallopeptidases; Metalloproteases; Metalloproteinases; Methods; Mice; Mice, Knock-out; Mice, Knockout; Modeling; Modification; Molecular; Molecular Interaction; Monolayer culture; Motility; Motility, Cellular; Murine; Mus; Muscle Development; Muscular Development; Null Mouse; Organ Culture; Organ Culture Techniques; Pancreas Cancer; Pancreatic Cancer; Pathway interactions; Pattern; Post-Transcriptional Gene Silencing; Post-Transcriptional Gene Silencings; Posttranscriptional Gene Silencing; Posttranscriptional Gene Silencings; Process; Proteoheparan Sulfate; Pseudomonas Infections; Pulmonary Body System; Pulmonary Organ System; Quelling; RNA Interference; RNA Silencing; RNA Silencings; RNAi; Reagent; Receptor Protein; Regulation; Research Resources; Resources; Respiratory System; Respiratory System, Lung; Respiratory system (all sites); Role; SIS cytokines; Sequence-Specific Posttranscriptional Gene Silencing; Signal Transduction; Signal Transduction Systems; Signaling; Signaling Molecule; Site; Structure of alveolar epithelium; Structure of corneal epithelium; Sulfatases; Targetings, Gene; Testing; Tissues; Up-Regulation; Up-Regulation (Physiology); Upregulation; VEGFs; Vascular Endothelial Growth Factors; Vegf; Work; Wound Healing; Wound Repair; acute lung injury; adhesin; alveolar epithelium; biological signal transduction; cell growth; cell motility; chemoattractant cytokine; chemokine; corneal; corneal epithelial; corneal epithelium; corneal repair; cultured cell line; extracellular; functional restoration; imaging; in vivo; in vivo Model; inhibitor; inhibitor/antagonist; injured; injury and repair; insight; macromolecule; malignancy; metalloproteinase (general); microbial; migration; monolayer; morphogens; neoplasm/cancer; novel; pathogen; pathway; pulmonary; receptor; repair; repaired; respiratory tract; response; restore function; restore functionality; restore lost function; small molecule; social role; sulfation; tissue repair; tool; wound
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