Brent A Bell | University of Pennsylvania (original) (raw)
Papers by Brent A Bell
Investigative Ophthalmology & Visual Science, Apr 22, 2011
Investigative Ophthalmology & Visual Science, Jun 21, 2021
Investigative Ophthalmology & Visual Science, 2019
SummaryLack of non-muscleβ-actin gene (Actb) leads to early embryonic lethality in mice, however ... more SummaryLack of non-muscleβ-actin gene (Actb) leads to early embryonic lethality in mice, however mice withβ- toγ-actin replacement develop normally and show no detectable phenotypes at young age. Here we investigated the effect of this replacement in the retina. During aging, these mice have accelerated de-generation of retinal structure and function, including elongated microvilli and defective mitochondria of retinal pigment epithelium (RPE), abnormally bulging photoreceptor outer segments (OS) accompanied by reduced transducin concentration and light sensitivity, and accumulation of autofluorescent microglia cells in the subretinal space between RPE and OS. These defects are accompanied by changes in the F-actin binding of several key actin interacting partners, including ezrin, myosin, talin, and vinculin known to play central roles in modulating actin cytoskeleton and cell adhesion and mediating the phagocytosis of OS. Our data show thatβ-actin protein is essential for maintain...
Proceedings of SPIE, Feb 9, 2006
We have developed and used a laser optoacoustic imaging system with transrectal probe (LOIS-P) fo... more We have developed and used a laser optoacoustic imaging system with transrectal probe (LOIS-P) for detection of mechanical lesions in canine prostates in vivo. LOIS images have been acquired with a 128-channel transrectal probe and a 32-channel data acquisition ...
Investigative Ophthalmology & Visual Science, Jun 10, 2020
Investigative Ophthalmology & Visual Science, May 10, 2007
Investigative Ophthalmology & Visual Science, 2018
Proceedings of Inter-Institute Workshop on In Vivo Optical Imaging at the NIH
Confocal opto-acoustic transducer (COAT) was developed and applied for detection of early stages ... more Confocal opto-acoustic transducer (COAT) was developed and applied for detection of early stages of squamous cell carcinoma in hamster model of oral cancer. COAT is a novel imaging modality capable of detecting profiles of wide-band ultrasonic transients at the site of pulsed laser irradiation. Animal model of oral cancer used Syrian golden hamsters treated with carcinogenic agent, DMBA (9,10-Dimethyl-1,2-Benzanthracene). Opto-acoustic tomography was applied to visualize the course of cancer development from normal to displasia, to carcinoma in situ, to invasive carcinoma. Correlation of the opto-acoustic images with H&E histology sections confirmed that early cancer lesions, invisible by gross observation, could be detected with the opto-acoustic tomography. Our hypothesis is that pronounced contrast revealed by the opto-acoustic tomography between normal and malignant tissues is associated with increased sizes and concentration of cellular nuclei at the stage of microscopic displa...
Experimental Eye Research, Sep 1, 2015
CC chemokine ligand 2 (CCL2) recruits macrophages to reduce inflammatory responses. Decayaccelera... more CC chemokine ligand 2 (CCL2) recruits macrophages to reduce inflammatory responses. Decayaccelerating factor (DAF) is a membrane regulator of the classical and alternative pathways of complement activation. In view of the link between complement genes and retinal diseases, we evaluated the retinal phenotype of C57BL/6J mice and mice lacking Ccl2 and/or Daf1 at 12 months of age, using scanning laser ophthalmoscopic imaging, electroretinography (ERG), histology, immunohistochemistry, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis. In comparison to C57BL/6J mice, mutant mice had an increased number of autofluorescent foci, with the greatest number in the Ccl2 −/− /Daf1 −/− retina. ERG amplitudes in Ccl2 −/− /Daf1 −/− , Ccl2 −/− and Daf1 −/− mice were reduced, with the greatest reduction in Ccl2 −/− /Daf1 −/− mice. TUNEL-positive cells were not seen in C57BL/6J retina, but were prevalent in the outer and inner nuclear layers of Ccl2 −/− Daf1 −/− mice and were present at reduced density in Ccl2 −/− or Daf1 −/− mice. Cell loss was most pronounced in the outer and inner nuclear layers of Ccl2 −/− /Daf1 −/− mice. The levels of the endoplasmic reticulum chaperone GPR78 and transcription factor ATF4 were significantly increased in the Ccl2 −/− /Daf1 −/− retina. In comparison to the C57BL/6J retina, the phosphorylation of NF-κB p65, p38, ERK and JNK was significantly upregulated while SIRT1 was significantly downregulated in the Ccl2 −/− /Daf1 −/− retina. Our results suggest that loss of Ccl2 and Daf1 causes retinal neuronal death and degeneration which is related to increased endoplasmic reticulum stress, oxidative stress and inflammation.
Journal of Leukocyte Biology, Sep 22, 2015
Recent studies have suggested that reagents inhibiting complement activation could be effective i... more Recent studies have suggested that reagents inhibiting complement activation could be effective in treating T cell mediated autoimmune diseases such as autoimmune uveitis. However, the precise role of the complement anaphylatoxin receptors (C3a and C5a receptors) in the pathogenesis of autoimmune uveitis remains elusive and controversial. We induced experimental autoimmune uveitis in mice deficient or sufficient in both C3a and C5a receptors and rigorously compared their retinal phenotype using various imaging techniques, including indirect ophthalmoscopy, confocal scanning laser ophthalmoscopy, spectral domain optical coherence tomography, topical endoscopic fundus imaging, and histopathological analysis. We also assessed retinal function using electroretinography. Moreover, we performed Ag-specific T cell recall assays and T cell adoptive transfer experiments to compare pathogenic T cell activity between wild-type and knockout mice with experimental autoimmune uveitis. These experiments showed that C3a receptor/C5a receptor-deficient mice developed much less severe uveitis than did control mice using all retinal examination methods and that these mice had reduced pathogenic T cell responses. Our data demonstrate that both complement anaphylatoxin receptors are important for the development of experimental autoimmune uveitis, suggesting that targeting these receptors could be a valid approach for treating patients with autoimmune uveitis.
The FASEB Journal, Jun 29, 2022
Investigative Ophthalmology & Visual Science, Jun 11, 2015
Investigative Ophthalmology & Visual Science, Apr 30, 2014
Investigative Ophthalmology & Visual Science, Jun 23, 2017
JCI insight, Sep 22, 2022
Cub domain-containing protein 1 (CDCP1) is a surface protein highly expressed on the surface of m... more Cub domain-containing protein 1 (CDCP1) is a surface protein highly expressed on the surface of many cancer cells, however, the distribution of CDCP1 in normal tissues and its potential roles in non-tumor cells are poorly understood. We previously reported that CDCP1 interacts with CD6, a surface marker of T cells, suggesting that it is a novel immunoregulator, but the physiological significance of the newly discovered CDCP1-CD6 interaction remains unclear. In this report, we found that CDCP1 is present on both human and mouse retinal pigmented epithelial cells (RPEs), a component of the blood-retina barrier (BRB), using a new anti-CDCP1 monoclonal antibody that we developed. CDCP1 knockout (KO) mice on two different genetic backgrounds both developed significantly attenuated retinal T cell infiltration and uveitis after adoptive transfer of pre-activated pathogenic T cells in a model of autoimmune uveitis. We also found that tight junctions were severely disrupted with infiltrating T cells detected in the RPE flat mounts prepared from the WT but not CDCP1 KO mice during EAU development. Mechanistically, we discovered that CDCP1 on RPE was upregulated by IFNγ in vitro and after EAU induction in vivo. CD6 stimulation induced significantly increased RPE barrier permeability of WT, but not CDCP1 knockdown (KD) RPE, and activated T cells migrated through the WT RPE monolayes more efficiently than the CDCP1 KD RPE monolayers. In addition, CD6 stimulation of WT, but not the CDCP1 KD RPEs, induced massive stress fiber formation and focal adhesion disruption to reduce cell barrier tight junctions. These data suggest that CDCP1 on RPEs interacts with CD6 on T cells to induce RPE cytoskeleton remodeling and focal adhesion disruption, which open up the tight junctions to facilitate T cell infiltration for the development of uveitis.
Investigative Ophthalmology & Visual Science, Apr 22, 2011
Investigative Ophthalmology & Visual Science, Jun 21, 2021
Investigative Ophthalmology & Visual Science, 2019
SummaryLack of non-muscleβ-actin gene (Actb) leads to early embryonic lethality in mice, however ... more SummaryLack of non-muscleβ-actin gene (Actb) leads to early embryonic lethality in mice, however mice withβ- toγ-actin replacement develop normally and show no detectable phenotypes at young age. Here we investigated the effect of this replacement in the retina. During aging, these mice have accelerated de-generation of retinal structure and function, including elongated microvilli and defective mitochondria of retinal pigment epithelium (RPE), abnormally bulging photoreceptor outer segments (OS) accompanied by reduced transducin concentration and light sensitivity, and accumulation of autofluorescent microglia cells in the subretinal space between RPE and OS. These defects are accompanied by changes in the F-actin binding of several key actin interacting partners, including ezrin, myosin, talin, and vinculin known to play central roles in modulating actin cytoskeleton and cell adhesion and mediating the phagocytosis of OS. Our data show thatβ-actin protein is essential for maintain...
Proceedings of SPIE, Feb 9, 2006
We have developed and used a laser optoacoustic imaging system with transrectal probe (LOIS-P) fo... more We have developed and used a laser optoacoustic imaging system with transrectal probe (LOIS-P) for detection of mechanical lesions in canine prostates in vivo. LOIS images have been acquired with a 128-channel transrectal probe and a 32-channel data acquisition ...
Investigative Ophthalmology & Visual Science, Jun 10, 2020
Investigative Ophthalmology & Visual Science, May 10, 2007
Investigative Ophthalmology & Visual Science, 2018
Proceedings of Inter-Institute Workshop on In Vivo Optical Imaging at the NIH
Confocal opto-acoustic transducer (COAT) was developed and applied for detection of early stages ... more Confocal opto-acoustic transducer (COAT) was developed and applied for detection of early stages of squamous cell carcinoma in hamster model of oral cancer. COAT is a novel imaging modality capable of detecting profiles of wide-band ultrasonic transients at the site of pulsed laser irradiation. Animal model of oral cancer used Syrian golden hamsters treated with carcinogenic agent, DMBA (9,10-Dimethyl-1,2-Benzanthracene). Opto-acoustic tomography was applied to visualize the course of cancer development from normal to displasia, to carcinoma in situ, to invasive carcinoma. Correlation of the opto-acoustic images with H&E histology sections confirmed that early cancer lesions, invisible by gross observation, could be detected with the opto-acoustic tomography. Our hypothesis is that pronounced contrast revealed by the opto-acoustic tomography between normal and malignant tissues is associated with increased sizes and concentration of cellular nuclei at the stage of microscopic displa...
Experimental Eye Research, Sep 1, 2015
CC chemokine ligand 2 (CCL2) recruits macrophages to reduce inflammatory responses. Decayaccelera... more CC chemokine ligand 2 (CCL2) recruits macrophages to reduce inflammatory responses. Decayaccelerating factor (DAF) is a membrane regulator of the classical and alternative pathways of complement activation. In view of the link between complement genes and retinal diseases, we evaluated the retinal phenotype of C57BL/6J mice and mice lacking Ccl2 and/or Daf1 at 12 months of age, using scanning laser ophthalmoscopic imaging, electroretinography (ERG), histology, immunohistochemistry, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis. In comparison to C57BL/6J mice, mutant mice had an increased number of autofluorescent foci, with the greatest number in the Ccl2 −/− /Daf1 −/− retina. ERG amplitudes in Ccl2 −/− /Daf1 −/− , Ccl2 −/− and Daf1 −/− mice were reduced, with the greatest reduction in Ccl2 −/− /Daf1 −/− mice. TUNEL-positive cells were not seen in C57BL/6J retina, but were prevalent in the outer and inner nuclear layers of Ccl2 −/− Daf1 −/− mice and were present at reduced density in Ccl2 −/− or Daf1 −/− mice. Cell loss was most pronounced in the outer and inner nuclear layers of Ccl2 −/− /Daf1 −/− mice. The levels of the endoplasmic reticulum chaperone GPR78 and transcription factor ATF4 were significantly increased in the Ccl2 −/− /Daf1 −/− retina. In comparison to the C57BL/6J retina, the phosphorylation of NF-κB p65, p38, ERK and JNK was significantly upregulated while SIRT1 was significantly downregulated in the Ccl2 −/− /Daf1 −/− retina. Our results suggest that loss of Ccl2 and Daf1 causes retinal neuronal death and degeneration which is related to increased endoplasmic reticulum stress, oxidative stress and inflammation.
Journal of Leukocyte Biology, Sep 22, 2015
Recent studies have suggested that reagents inhibiting complement activation could be effective i... more Recent studies have suggested that reagents inhibiting complement activation could be effective in treating T cell mediated autoimmune diseases such as autoimmune uveitis. However, the precise role of the complement anaphylatoxin receptors (C3a and C5a receptors) in the pathogenesis of autoimmune uveitis remains elusive and controversial. We induced experimental autoimmune uveitis in mice deficient or sufficient in both C3a and C5a receptors and rigorously compared their retinal phenotype using various imaging techniques, including indirect ophthalmoscopy, confocal scanning laser ophthalmoscopy, spectral domain optical coherence tomography, topical endoscopic fundus imaging, and histopathological analysis. We also assessed retinal function using electroretinography. Moreover, we performed Ag-specific T cell recall assays and T cell adoptive transfer experiments to compare pathogenic T cell activity between wild-type and knockout mice with experimental autoimmune uveitis. These experiments showed that C3a receptor/C5a receptor-deficient mice developed much less severe uveitis than did control mice using all retinal examination methods and that these mice had reduced pathogenic T cell responses. Our data demonstrate that both complement anaphylatoxin receptors are important for the development of experimental autoimmune uveitis, suggesting that targeting these receptors could be a valid approach for treating patients with autoimmune uveitis.
The FASEB Journal, Jun 29, 2022
Investigative Ophthalmology & Visual Science, Jun 11, 2015
Investigative Ophthalmology & Visual Science, Apr 30, 2014
Investigative Ophthalmology & Visual Science, Jun 23, 2017
JCI insight, Sep 22, 2022
Cub domain-containing protein 1 (CDCP1) is a surface protein highly expressed on the surface of m... more Cub domain-containing protein 1 (CDCP1) is a surface protein highly expressed on the surface of many cancer cells, however, the distribution of CDCP1 in normal tissues and its potential roles in non-tumor cells are poorly understood. We previously reported that CDCP1 interacts with CD6, a surface marker of T cells, suggesting that it is a novel immunoregulator, but the physiological significance of the newly discovered CDCP1-CD6 interaction remains unclear. In this report, we found that CDCP1 is present on both human and mouse retinal pigmented epithelial cells (RPEs), a component of the blood-retina barrier (BRB), using a new anti-CDCP1 monoclonal antibody that we developed. CDCP1 knockout (KO) mice on two different genetic backgrounds both developed significantly attenuated retinal T cell infiltration and uveitis after adoptive transfer of pre-activated pathogenic T cells in a model of autoimmune uveitis. We also found that tight junctions were severely disrupted with infiltrating T cells detected in the RPE flat mounts prepared from the WT but not CDCP1 KO mice during EAU development. Mechanistically, we discovered that CDCP1 on RPE was upregulated by IFNγ in vitro and after EAU induction in vivo. CD6 stimulation induced significantly increased RPE barrier permeability of WT, but not CDCP1 knockdown (KD) RPE, and activated T cells migrated through the WT RPE monolayes more efficiently than the CDCP1 KD RPE monolayers. In addition, CD6 stimulation of WT, but not the CDCP1 KD RPEs, induced massive stress fiber formation and focal adhesion disruption to reduce cell barrier tight junctions. These data suggest that CDCP1 on RPEs interacts with CD6 on T cells to induce RPE cytoskeleton remodeling and focal adhesion disruption, which open up the tight junctions to facilitate T cell infiltration for the development of uveitis.