Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ...
Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ... Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ...
Illustrations LegendsBIOMEDICAL ENGINEERING—PAGE 11Top Left Triad: Stem Cell technology, the laboratory of George Muschler, M.D. Left Image: In Situ hybridizationexpression of Collagen Type 1 on day 6 Human CTPs in vitro. Control hybridized with sense to bothCbfa 1 and BMP6. Center Image: Proliferation of Human CTPs and Expression of Alkaline Phosphatase onLoaded Coralline HA disks, day 9 culture. Graphic Image on right: Schematic diagram of the osteoblasticstem cell system. This conceptual drawing illustrates the primary candidate populations of stem cells and transitcells thought to be associated with bone formation and remodeling: Vascular pericytes (green), Westen-Baintoncells (orange), type I or pre-osteoblasts (pink), secretory osteoblasts (maroon), osteocytes (brown), liningcells (purple), and adipocytes (yellow). Vascular pericytes may give rise to the Westen-Bainton cells. Pericytesand Westen-Bainton cells may contribute to the formation of pre-osteoblasts and also adipocytes. New osteoblastare added in the region immediately behind the advancing front of osteoclastic resorption. Secretory osteoblastsproduce new bone matrix until they become quiescent on the surface of bone as a lining cells (purple)or become embedded in the matrix as osteocytes (brown), or die via apoptosis. Osteoclast formation is also illustrated.A fraction of the monocytes population in systemic circulation (blue) will become resident in thebone marrow space. Osteoclasts are formed by fusion of monocytes resident in bone marrow to form multinucleatedfunctional units. The nuclei in active osteoclasts continue to be turned over as a result of nuclear lossand ongoing fusion events with new marrow derived monocytes. The black arrow indicates the direction of boneresorption by the osteoclastic front, followed by bone formation.Double panel, top right: Normal human femur contrasted with Human femur degenerated by osteoporosis(Top right twin panels). Images generated with high-resolution micro-CT, a 3D x-ray imaging technology, to evaluatebone microarchitecture in early bone loss and bone formation in the laboratory of Kimerly Powell, Ph.D.Central image: An array of microneedles (center image) 30 mm wide by 300 mm high in development in theBiological Micro Electrical Mechanisms Systems laboratory of Shuvo Roy, Ph.D. and Aaron Fleischman, Ph.D.Lower panel: “Biomechanics of a walk.” Graphic (lower panel) provided by Ton van den Bogert, Ph.D., BiomechanicsLaboratory.CANCER BIOLOGY—PAGE 44Top figure: Diagram illustrating the progression of prostate cancer. Human prostate cancer involves stagesthat correlate with loss of tumor suppressor genes. From Robert Silverman, Ph.D.Middle figure:Model hereditary prostate cancer family. From Graham Casey, Ph.D.Bottom figure: Immunohistochemical analysis of the expression of RNase L protein in a prostate tumor specimenfrom a mutation carrier. The cytoplasm of normal prostate epithelium stains positively (arrow on right),whereas the tumor cells are negative (arrow on left). From Robert Silverman, Ph.D.CELL BIOLOGY—PAGE 65Top image: Distribution of EGFP-fascin in a syndecan-1-activated cell, (top image). Activation of syndecan-1,by cell attachment to surfaces coated with either syndecan-1 antibody or thrombospondin-1, results in lamellipodialcell spreading and recruitment of fascin into the core F-actin bundles of microspikes and filopodia. Illustrationfrom the laboratory of Jo Adams.Lower Panels: Confocal micrographs showing surface binding (lower left) and internalization (lower right) ofHDL 2(red) and HDL 3(green) mediated by the scavenger receptor Bl in cultured adrenal cells. Areas of HDL 2and HDL 3colocalization are yellow. Images by Diane Green, B.S0., from the laboratory of Rick Morton, Ph.D.,with Judy Drazba, Ph.D., Imaging Core.IMMUNOLOGY — PAGE 85Top image: Normal T cells (nuclei DAPI stained, small blue) become trapped in the Hyaluronic Acid (HA) (FITCstained, green) cables formed on a renal cell carcinoma cell line (nuclei DAPI stained, large blue), SK-RC-45.The HA ligand, CD44 (Alexa 568 stained, red), can be seen on both the RCC line and the T cells.Mark Thornton, from Dr. Jim Finke’s lab.Lower image: Confocal micrograph of poly I:C-treated mouse colon parenchymal cells. Hyaluronan (green),TNF-stimulated gene 6 (TSG-6) (red) and nuclei (blue) are fluorescently labeled in this image. From de laMotte, C., Drazba, J., Hascall, V., Day, A., and S. Strong.198
MOLECULAR BIOLOGY — PAGE 101Confocal micrograph of mouse colon tissue from an animal treated with dextran sulfate to induce experimentalcolitis. Sections were fluorescently labeled for hyaluronan (green), inter-alpha inhibitor (red) and nuclei (blue).Image produced in the laboratory of Ganesh Sen, Ph.D. From Kessler, S., de la Motte, C., Drazba, J., Sen,G., and S. Strong.MOLECULAR CARDIOLOGY — PAGE 118Top image: Molecular surface of PINCH LIM domain involved in mediating cell adhesion. The regions coloredin blue are involved in protein-protein recognition in focal adhesion assembly. From the laboratory of Jun Qin,Ph.D.Middle image on right: Agonist binding pocket of the α1-Adrenergic Receptor. A molecular model of theα1A-AR as shown from the extracellular surface. Alpha-carbon coordinates were taken from the bacteriorhodopsinmodel and adjusted based upon the results of several mutagenesis studies from the laboratory of DiannePerez, Ph.D. Residues that been identified to be involved in agonist binding are shown in space-filled representationand are listed under its respective transmembrane domain (TM) in order from the extracellular surface.Amino acid residues are numbered according to the rat α1A-AR sequence.Lower image: Vitamin K-dependent (VKD) proteins are modified by the VKD- or gamma-carboxylase, an integralmembrane enzyme that resides in the endoplasmic reticulum. Carboxylation occurs during the secretion ofVKD proteins in a process that is poorly understood. The VKD proteins have a sequence (the pink rectangle)that the carboxylase binds with high affinity, which selectively targets VKD proteins for carboxylation. Thecarboxylase uses the oxygenation of vitamin K hydroquinone (KH 2, illustrated by the orange napthoquinone) tovitamin K epoxide (KO) to convert glutamic acid residues in VKD proteins to carboxylated glutamic acids (indicatedby white Y’s). Clusters of glutamic acids are modified (3 in this example) to render the VKD proteinsactive in functions that include hemostasis, growth control, bone metabolism and signal transduction. Normally,fully carboxylated VKD proteins are generated; however, conditions that limit the supply of KH 2block carboxylationand result in the secretion of uncarboxylated- and partially-carboxylated forms of inactive VKD proteins.Warfarin limits KH 2by inhibiting the reductase that regenerates KH 2from KO and is a commonly-used anticoagulant.From the laboratory of Kathy Berkner, Ph.D.NEUROSCIENCES — PAGE 133Lower left and right, uppermost central panel: Cultured hippocampal neurons immunofluorescently stainedfor syntaxin (red) and neurofilament (green). Images by Xiaoquin Liu, from the laboratory of Mark Perin, Ph.D.Central middle and lower panel: In situ hybridization for ephrin mRNAs and ligands in embryonic chick cerebellum,detected using alkaline phosphatase substrate. Reproduced from Nishida et al., 2002, Development129:5647-58 with permission.Background and remaining panels: Oligodendrocytes and oligodendrocyte progenitors expressing enhancedgreen fluorescent protein and immunolabeled for NG2 proteoglycan (red). Reproduced from Mallon et al., 2002,Journal of Neuroscience 22: 876-85 with permission.Page design by Graham Kidd, Ph.D., Department of Neuroscience.CENTERS OF RESEARCH — PAGE 153Top image: Molecular surface of PINCH LIM domain involved in mediating cell adhesion. The regions coloredin blue are involved in protein-protein recognition in focal adhesion assembly. From the laboratory of Jun Qin,Ph.D.Middle image: Three dimensional backbone trace of PINCH LIM domain involved in mediating cell adhesion.Regions involved in protein recognition are highlighted by amino side chains (blue). From the laboratory of JunQin, Ph.D.Lower image: A biological “Trojan Horse” utilizing receptor-mediated Cbl uptake as a means of targeting NO-Cbl to neoplasms. Nitrosylcobalamin (NO-Cbl) is delivered to cells bound to plasma transcobalamin II (TC II).TC II, a non-glycosylated plasma protein (43-kD), binds to specific cell surface receptors (TC II-R) that recognizethe TC II-Cbl complex (holo-TC II) preferentially to apoTC II (TC II alone). The TC II-R:TC II:NO-Cbl complexis internalized via endocytosis and TC II-NO-Cbl is delivered to lysosomes where NO is released fromCbl, and TC II is subsequently degraded. The chemotherapeutic effectiveness of NO-Cbl is based on the cytotoxicproperties of nitric oxide (NO). NO is oxidized from NO-Cbl in lysosomes at acidic pH. The NO free radicalinduces cytotoxicity through increased oxidative stress, inhibition of cellular metabolism, and direct DNAdamage, leading to apoptosis and/or necrosis. By Joseph Bauer, Ph.D., in the laboratory of Dan Lindner,M.D., Ph.D.Continued on Page 200199
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Illustrations LegendsBIOMEDICAL ENGINEERING—PAGE 11Top Left Triad: Stem Cell technology, the laboratory of George Muschler, M.D. Left Image: In Situ hybridizationexpression of Collagen Type 1 on day 6 Human CTPs in vitro. Control hybridized with sense to bothCbfa 1 and BMP6. Center Image: Proliferation of Human CTPs and Expression of Alkaline Phosphatase onLoaded Coralline HA disks, day 9 culture. Graphic Image on right: Schematic diagram of the osteoblasticstem cell system. This conceptual drawing illustrates the primary candidate populations of stem cells and transitcells thought to be associated with bone formation and remodeling: Vascular pericytes (green), Westen-Baintoncells (orange), type I or pre-osteoblasts (pink), secretory osteoblasts (maroon), osteocytes (brown), liningcells (purple), and adipocytes (yellow). Vascular pericytes may give rise to the Westen-Bainton cells. Pericytesand Westen-Bainton cells may contribute to the formation of pre-osteoblasts and also adipocytes. New osteoblastare added in the region immediately behind the advancing front of osteoclastic resorption. Secretory osteoblastsproduce new bone matrix until they become quiescent on the surface of bone as a lining cells (purple)or become embedded in the matrix as osteocytes (brown), or die via apoptosis. Osteoclast formation is also illustrated.A fraction of the monocytes population in systemic circulation (blue) will become resident in thebone marrow space. Osteoclasts are formed by fusion of monocytes resident in bone marrow to form multinucleatedfunctional units. The nuclei in active osteoclasts continue to be turned over as a result of nuclear lossand ongoing fusion events with new marrow derived monocytes. The black arrow indicates the direction of boneresorption by the osteoclastic front, followed by bone formation.Double panel, top right: Normal human femur contrasted with Human femur degenerated by osteoporosis(Top right twin panels). Images generated with high-resolution micro-CT, a 3D x-ray imaging technology, to evaluatebone microarchitecture in early bone loss and bone formation in the laboratory of Kimerly Powell, Ph.D.Central image: An array of microneedles (center image) 30 mm wide by 300 mm high in development in theBiological Micro Electrical Mechanisms Systems laboratory of Shuvo Roy, Ph.D. and Aaron Fleischman, Ph.D.Lower panel: “Biomechanics of a walk.” Graphic (lower panel) provided by Ton van den Bogert, Ph.D., BiomechanicsLaboratory.CANCER BIOLOGY—PAGE 44Top figure: Diagram illustrating the progression of prostate cancer. Human prostate cancer involves stagesthat correlate with loss of tumor suppressor genes. From Robert Silverman, Ph.D.Middle figure:Model hereditary prostate cancer family. From Graham Casey, Ph.D.Bottom figure: Immunohistochemical analysis of the expression of RNase L protein in a prostate tumor specimenfrom a mutation carrier. The cytoplasm of normal prostate epithelium stains positively (arrow on right),whereas the tumor cells are negative (arrow on left). From Robert Silverman, Ph.D.CELL BIOLOGY—PAGE 65Top image: Distribution of EGFP-fascin in a syndecan-1-activated cell, (top image). Activation of syndecan-1,by cell attachment to surfaces coated with either syndecan-1 antibody or thrombospondin-1, results in lamellipodialcell spreading and recruitment of fascin into the core F-actin bundles of microspikes and filopodia. Illustrationfrom the laboratory of Jo Adams.Lower Panels: Confocal micrographs showing surface binding (lower left) and internalization (lower right) ofHDL 2(red) and HDL 3(green) mediated by the scavenger receptor Bl in cultured adrenal cells. Areas of HDL 2and HDL 3colocalization are yellow. Images by Diane Green, B.S0., from the laboratory of Rick Morton, Ph.D.,with Judy Drazba, Ph.D., Imaging Core.IMMUNOLOGY — PAGE 85Top image: Normal T cells (nuclei DAPI stained, small blue) become trapped in the Hyaluronic Acid (HA) (FITCstained, green) cables formed on a renal cell carcinoma cell line (nuclei DAPI stained, large blue), SK-RC-45.The HA ligand, CD44 (Alexa 568 stained, red), can be seen on both the RCC line and the T cells.Mark Thornton, from Dr. Jim Finke’s lab.Lower image: Confocal micrograph of poly I:C-treated mouse colon parenchymal cells. Hyaluronan (green),TNF-stimulated gene 6 (TSG-6) (red) and nuclei (blue) are fluorescently labeled in this image. From de laMotte, C., Drazba, J., Hascall, V., Day, A., and S. Strong.198
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