The Experts below are selected from a list of 693 Experts worldwide ranked by ideXlab platform
Ulrich F. O. Luhmann - One of the best experts on this subject based on the ideXlab platform.
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the severity of Retinal pathology in homozygous crb1rd8 rd8 mice is dependent on additional genetic factors
Human Molecular Genetics, 2015Co-Authors: Ulrich F. O. Luhmann, Livia S. Carvalho, Sophia-martha Kleine Holthaus, Jill A. Cowing, Simon Greenaway, Colin J Chu, Philipp Herrmann, Alexander J. Smith, Peter M. G. Munro, Paul K. PotterAbstract:Understanding phenotype-genotype correlations in Retinal degeneration is a major challenge. Mutations in CRB1 lead to a spectrum of autosomal recessive Retinal dystrophies with variable phenotypes suggesting the influence of modifying factors. To establish the contribution of the genetic background to phenotypic variability associated with the Crb1(rd8/rd8) mutation, we compared the Retinal pathology of Crb1(rd8/rd8)/J inbred mice with that of two Crb1(rd8/rd8) lines backcrossed with C57BL/6JOlaHsd mice. Topical endoscopic fundal imaging and scanning laser ophthalmoscopy fundus images of all three Crb1(rd8/rd8) lines showed a significant increase in the number of inferior Retinal lesions that was strikingly variable between the lines. Optical coherence tomography, semithin, ultrastructural morphology and assessment of inflammatory and vascular marker by immunohistochemistry and quantitative reverse transcriptase-polymerase chain reaction revealed that the lesions were associated with photoreceptor death, Muller and microglia activation and Telangiectasia-like vascular remodelling-features that were stable in the inbred, variable in the second, but virtually absent in the third Crb1(rd8/rd8) line, even at 12 months of age. This suggests that the Crb1(rd8/rd8) mutation is necessary, but not sufficient for the development of these degenerative features. By whole-genome SNP analysis of the genotype-phenotype correlation, a candidate region on chromosome 15 was identified. This may carry one or more genetic modifiers for the manifestation of the Retinal pathology associated with mutations in Crb1. This study also provides insight into the nature of the Retinal vascular lesions that likely represent a clinical correlate for the formation of Retinal Telangiectasia or Coats-like vasculopathy in patients with CRB1 mutations that are thought to depend on such genetic modifiers.
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The severity of Retinal pathology in homozygous Crb1rd8/rd8 mice is dependent on additional genetic factors
Human molecular genetics, 2014Co-Authors: Ulrich F. O. Luhmann, Livia S. Carvalho, Sophia-martha Kleine Holthaus, Jill A. Cowing, Simon Greenaway, Colin J Chu, Philipp Herrmann, Alexander J. Smith, Peter M. G. Munro, Paul K. PotterAbstract:Understanding phenotype-genotype correlations in Retinal degeneration is a major challenge. Mutations in CRB1 lead to a spectrum of autosomal recessive Retinal dystrophies with variable phenotypes suggesting the influence of modifying factors. To establish the contribution of the genetic background to phenotypic variability associated with the Crb1(rd8/rd8) mutation, we compared the Retinal pathology of Crb1(rd8/rd8)/J inbred mice with that of two Crb1(rd8/rd8) lines backcrossed with C57BL/6JOlaHsd mice. Topical endoscopic fundal imaging and scanning laser ophthalmoscopy fundus images of all three Crb1(rd8/rd8) lines showed a significant increase in the number of inferior Retinal lesions that was strikingly variable between the lines. Optical coherence tomography, semithin, ultrastructural morphology and assessment of inflammatory and vascular marker by immunohistochemistry and quantitative reverse transcriptase-polymerase chain reaction revealed that the lesions were associated with photoreceptor death, Muller and microglia activation and Telangiectasia-like vascular remodelling-features that were stable in the inbred, variable in the second, but virtually absent in the third Crb1(rd8/rd8) line, even at 12 months of age. This suggests that the Crb1(rd8/rd8) mutation is necessary, but not sufficient for the development of these degenerative features. By whole-genome SNP analysis of the genotype-phenotype correlation, a candidate region on chromosome 15 was identified. This may carry one or more genetic modifiers for the manifestation of the Retinal pathology associated with mutations in Crb1. This study also provides insight into the nature of the Retinal vascular lesions that likely represent a clinical correlate for the formation of Retinal Telangiectasia or Coats-like vasculopathy in patients with CRB1 mutations that are thought to depend on such genetic modifiers.
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Differential Modulation of Retinal Degeneration by Ccl2 and Cx3cr1 Chemokine Signalling
2013Co-Authors: Ulrich F. O. Luhmann, Livia S. Carvalho, Jill A. Cowing, Peter M. G. Munro, Hannah E J Armer, Vy Luong, Robert E. Maclaren, Clemens A. Lange, Scott Robbie, Frederick W. FitzkeAbstract:Microglia and macrophages are recruited to sites of Retinal degeneration where local cytokines and chemokines determine protective or neurotoxic microglia responses. Defining the role of Ccl2-Ccr2 and Cx3cl1-Cx3cr1 signalling for Retinal pathology is of particular interest because of its potential role in age-related macular degeneration (AMD). Ccl2, Ccr2, and Cx3cr1 signalling defects impair macrophage trafficking, but have, in several conflicting studies, been reported to show different degrees of age-related Retinal degeneration. Ccl2/Cx3cr1 double knockout (CCDKO) mice show an early onset Retinal degeneration and have been suggested as a model for AMD. In order to understand phenotypic discrepancies in different chemokine knockout lines and to study how defects in Ccl2 and/or Cx3cr1 signalling contribute to the described early onset Retinal degeneration, we defined primary and secondary pathological events in CCDKO mice. To control for genetic background variability, we compared the original phenotype with that of single Ccl2, Cx3cr1 and Ccl2/Cx3cr1 double knockout mice obtained from backcrosses of CCDKO with C57Bl/6 mice. We found that the primary pathological event in CCDKO mice develops in the inferior outer nuclear layer independently of light around postnatal day P14. RPE and vascular lesions develop secondarily with increasing penetrance with age and are clinically similar to Retinal Telangiectasia not to choroidal neovascularisation. Furthermore, we provide evidence that a third autosomal recessive gene causes the degeneration in CCDKO mice and in all affected re-derived lines and subsequently demonstrated co-segregation of th
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Differential Modulation of Retinal Degeneration by Ccl2 and Cx3cr1 Chemokine Signalling
PloS one, 2012Co-Authors: Ulrich F. O. Luhmann, Livia S. Carvalho, Jill A. Cowing, Peter M. G. Munro, Clemens Lange, Scott J. Robbie, Hannah E J Armer, Vy Luong, Robert E. Maclaren, Frederick W. FitzkeAbstract:Microglia and macrophages are recruited to sites of Retinal degeneration where local cytokines and chemokines determine protective or neurotoxic microglia responses. Defining the role of Ccl2-Ccr2 and Cx3cl1-Cx3cr1 signalling for Retinal pathology is of particular interest because of its potential role in age-related macular degeneration (AMD). Ccl2, Ccr2, and Cx3cr1 signalling defects impair macrophage trafficking, but have, in several conflicting studies, been reported to show different degrees of age-related Retinal degeneration. Ccl2/Cx3cr1 double knockout (CCDKO) mice show an early onset Retinal degeneration and have been suggested as a model for AMD. In order to understand phenotypic discrepancies in different chemokine knockout lines and to study how defects in Ccl2 and/or Cx3cr1 signalling contribute to the described early onset Retinal degeneration, we defined primary and secondary pathological events in CCDKO mice. To control for genetic background variability, we compared the original phenotype with that of single Ccl2, Cx3cr1 and Ccl2/Cx3cr1 double knockout mice obtained from backcrosses of CCDKO with C57Bl/6 mice. We found that the primary pathological event in CCDKO mice develops in the inferior outer nuclear layer independently of light around postnatal day P14. RPE and vascular lesions develop secondarily with increasing penetrance with age and are clinically similar to Retinal Telangiectasia not to choroidal neovascularisation. Furthermore, we provide evidence that a third autosomal recessive gene causes the degeneration in CCDKO mice and in all affected re-derived lines and subsequently demonstrated co-segregation of the naturally occurring RD8 mutation in the Crb1 gene. By comparing CCDKO mice with re-derived CCl2(-/-)/Crb1(Rd8/RD8), Cx3cr1(-/-)/Crb1(Rd8/RD8) and CCl2(-/-)/Cx3cr1(-/-)/Crb1(Rd8/RD8) mice, we observed a differential modulation of the Retinal phenotype by genetic background and both chemokine signalling pathways. These findings indicate that CCDKO mice are not a model of AMD, but a model for an inherited Retinal degeneration that is differentially modulated by Ccl2-Ccr2 and Cx3cl1-Cx3cr1 chemokine signalling.
Peter M. G. Munro - One of the best experts on this subject based on the ideXlab platform.
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the severity of Retinal pathology in homozygous crb1rd8 rd8 mice is dependent on additional genetic factors
Human Molecular Genetics, 2015Co-Authors: Ulrich F. O. Luhmann, Livia S. Carvalho, Sophia-martha Kleine Holthaus, Jill A. Cowing, Simon Greenaway, Colin J Chu, Philipp Herrmann, Alexander J. Smith, Peter M. G. Munro, Paul K. PotterAbstract:Understanding phenotype-genotype correlations in Retinal degeneration is a major challenge. Mutations in CRB1 lead to a spectrum of autosomal recessive Retinal dystrophies with variable phenotypes suggesting the influence of modifying factors. To establish the contribution of the genetic background to phenotypic variability associated with the Crb1(rd8/rd8) mutation, we compared the Retinal pathology of Crb1(rd8/rd8)/J inbred mice with that of two Crb1(rd8/rd8) lines backcrossed with C57BL/6JOlaHsd mice. Topical endoscopic fundal imaging and scanning laser ophthalmoscopy fundus images of all three Crb1(rd8/rd8) lines showed a significant increase in the number of inferior Retinal lesions that was strikingly variable between the lines. Optical coherence tomography, semithin, ultrastructural morphology and assessment of inflammatory and vascular marker by immunohistochemistry and quantitative reverse transcriptase-polymerase chain reaction revealed that the lesions were associated with photoreceptor death, Muller and microglia activation and Telangiectasia-like vascular remodelling-features that were stable in the inbred, variable in the second, but virtually absent in the third Crb1(rd8/rd8) line, even at 12 months of age. This suggests that the Crb1(rd8/rd8) mutation is necessary, but not sufficient for the development of these degenerative features. By whole-genome SNP analysis of the genotype-phenotype correlation, a candidate region on chromosome 15 was identified. This may carry one or more genetic modifiers for the manifestation of the Retinal pathology associated with mutations in Crb1. This study also provides insight into the nature of the Retinal vascular lesions that likely represent a clinical correlate for the formation of Retinal Telangiectasia or Coats-like vasculopathy in patients with CRB1 mutations that are thought to depend on such genetic modifiers.
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The severity of Retinal pathology in homozygous Crb1rd8/rd8 mice is dependent on additional genetic factors
Human molecular genetics, 2014Co-Authors: Ulrich F. O. Luhmann, Livia S. Carvalho, Sophia-martha Kleine Holthaus, Jill A. Cowing, Simon Greenaway, Colin J Chu, Philipp Herrmann, Alexander J. Smith, Peter M. G. Munro, Paul K. PotterAbstract:Understanding phenotype-genotype correlations in Retinal degeneration is a major challenge. Mutations in CRB1 lead to a spectrum of autosomal recessive Retinal dystrophies with variable phenotypes suggesting the influence of modifying factors. To establish the contribution of the genetic background to phenotypic variability associated with the Crb1(rd8/rd8) mutation, we compared the Retinal pathology of Crb1(rd8/rd8)/J inbred mice with that of two Crb1(rd8/rd8) lines backcrossed with C57BL/6JOlaHsd mice. Topical endoscopic fundal imaging and scanning laser ophthalmoscopy fundus images of all three Crb1(rd8/rd8) lines showed a significant increase in the number of inferior Retinal lesions that was strikingly variable between the lines. Optical coherence tomography, semithin, ultrastructural morphology and assessment of inflammatory and vascular marker by immunohistochemistry and quantitative reverse transcriptase-polymerase chain reaction revealed that the lesions were associated with photoreceptor death, Muller and microglia activation and Telangiectasia-like vascular remodelling-features that were stable in the inbred, variable in the second, but virtually absent in the third Crb1(rd8/rd8) line, even at 12 months of age. This suggests that the Crb1(rd8/rd8) mutation is necessary, but not sufficient for the development of these degenerative features. By whole-genome SNP analysis of the genotype-phenotype correlation, a candidate region on chromosome 15 was identified. This may carry one or more genetic modifiers for the manifestation of the Retinal pathology associated with mutations in Crb1. This study also provides insight into the nature of the Retinal vascular lesions that likely represent a clinical correlate for the formation of Retinal Telangiectasia or Coats-like vasculopathy in patients with CRB1 mutations that are thought to depend on such genetic modifiers.
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Differential Modulation of Retinal Degeneration by Ccl2 and Cx3cr1 Chemokine Signalling
2013Co-Authors: Ulrich F. O. Luhmann, Livia S. Carvalho, Jill A. Cowing, Peter M. G. Munro, Hannah E J Armer, Vy Luong, Robert E. Maclaren, Clemens A. Lange, Scott Robbie, Frederick W. FitzkeAbstract:Microglia and macrophages are recruited to sites of Retinal degeneration where local cytokines and chemokines determine protective or neurotoxic microglia responses. Defining the role of Ccl2-Ccr2 and Cx3cl1-Cx3cr1 signalling for Retinal pathology is of particular interest because of its potential role in age-related macular degeneration (AMD). Ccl2, Ccr2, and Cx3cr1 signalling defects impair macrophage trafficking, but have, in several conflicting studies, been reported to show different degrees of age-related Retinal degeneration. Ccl2/Cx3cr1 double knockout (CCDKO) mice show an early onset Retinal degeneration and have been suggested as a model for AMD. In order to understand phenotypic discrepancies in different chemokine knockout lines and to study how defects in Ccl2 and/or Cx3cr1 signalling contribute to the described early onset Retinal degeneration, we defined primary and secondary pathological events in CCDKO mice. To control for genetic background variability, we compared the original phenotype with that of single Ccl2, Cx3cr1 and Ccl2/Cx3cr1 double knockout mice obtained from backcrosses of CCDKO with C57Bl/6 mice. We found that the primary pathological event in CCDKO mice develops in the inferior outer nuclear layer independently of light around postnatal day P14. RPE and vascular lesions develop secondarily with increasing penetrance with age and are clinically similar to Retinal Telangiectasia not to choroidal neovascularisation. Furthermore, we provide evidence that a third autosomal recessive gene causes the degeneration in CCDKO mice and in all affected re-derived lines and subsequently demonstrated co-segregation of th
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Differential Modulation of Retinal Degeneration by Ccl2 and Cx3cr1 Chemokine Signalling
PloS one, 2012Co-Authors: Ulrich F. O. Luhmann, Livia S. Carvalho, Jill A. Cowing, Peter M. G. Munro, Clemens Lange, Scott J. Robbie, Hannah E J Armer, Vy Luong, Robert E. Maclaren, Frederick W. FitzkeAbstract:Microglia and macrophages are recruited to sites of Retinal degeneration where local cytokines and chemokines determine protective or neurotoxic microglia responses. Defining the role of Ccl2-Ccr2 and Cx3cl1-Cx3cr1 signalling for Retinal pathology is of particular interest because of its potential role in age-related macular degeneration (AMD). Ccl2, Ccr2, and Cx3cr1 signalling defects impair macrophage trafficking, but have, in several conflicting studies, been reported to show different degrees of age-related Retinal degeneration. Ccl2/Cx3cr1 double knockout (CCDKO) mice show an early onset Retinal degeneration and have been suggested as a model for AMD. In order to understand phenotypic discrepancies in different chemokine knockout lines and to study how defects in Ccl2 and/or Cx3cr1 signalling contribute to the described early onset Retinal degeneration, we defined primary and secondary pathological events in CCDKO mice. To control for genetic background variability, we compared the original phenotype with that of single Ccl2, Cx3cr1 and Ccl2/Cx3cr1 double knockout mice obtained from backcrosses of CCDKO with C57Bl/6 mice. We found that the primary pathological event in CCDKO mice develops in the inferior outer nuclear layer independently of light around postnatal day P14. RPE and vascular lesions develop secondarily with increasing penetrance with age and are clinically similar to Retinal Telangiectasia not to choroidal neovascularisation. Furthermore, we provide evidence that a third autosomal recessive gene causes the degeneration in CCDKO mice and in all affected re-derived lines and subsequently demonstrated co-segregation of the naturally occurring RD8 mutation in the Crb1 gene. By comparing CCDKO mice with re-derived CCl2(-/-)/Crb1(Rd8/RD8), Cx3cr1(-/-)/Crb1(Rd8/RD8) and CCl2(-/-)/Cx3cr1(-/-)/Crb1(Rd8/RD8) mice, we observed a differential modulation of the Retinal phenotype by genetic background and both chemokine signalling pathways. These findings indicate that CCDKO mice are not a model of AMD, but a model for an inherited Retinal degeneration that is differentially modulated by Ccl2-Ccr2 and Cx3cl1-Cx3cr1 chemokine signalling.
Jill A. Cowing - One of the best experts on this subject based on the ideXlab platform.
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the severity of Retinal pathology in homozygous crb1rd8 rd8 mice is dependent on additional genetic factors
Human Molecular Genetics, 2015Co-Authors: Ulrich F. O. Luhmann, Livia S. Carvalho, Sophia-martha Kleine Holthaus, Jill A. Cowing, Simon Greenaway, Colin J Chu, Philipp Herrmann, Alexander J. Smith, Peter M. G. Munro, Paul K. PotterAbstract:Understanding phenotype-genotype correlations in Retinal degeneration is a major challenge. Mutations in CRB1 lead to a spectrum of autosomal recessive Retinal dystrophies with variable phenotypes suggesting the influence of modifying factors. To establish the contribution of the genetic background to phenotypic variability associated with the Crb1(rd8/rd8) mutation, we compared the Retinal pathology of Crb1(rd8/rd8)/J inbred mice with that of two Crb1(rd8/rd8) lines backcrossed with C57BL/6JOlaHsd mice. Topical endoscopic fundal imaging and scanning laser ophthalmoscopy fundus images of all three Crb1(rd8/rd8) lines showed a significant increase in the number of inferior Retinal lesions that was strikingly variable between the lines. Optical coherence tomography, semithin, ultrastructural morphology and assessment of inflammatory and vascular marker by immunohistochemistry and quantitative reverse transcriptase-polymerase chain reaction revealed that the lesions were associated with photoreceptor death, Muller and microglia activation and Telangiectasia-like vascular remodelling-features that were stable in the inbred, variable in the second, but virtually absent in the third Crb1(rd8/rd8) line, even at 12 months of age. This suggests that the Crb1(rd8/rd8) mutation is necessary, but not sufficient for the development of these degenerative features. By whole-genome SNP analysis of the genotype-phenotype correlation, a candidate region on chromosome 15 was identified. This may carry one or more genetic modifiers for the manifestation of the Retinal pathology associated with mutations in Crb1. This study also provides insight into the nature of the Retinal vascular lesions that likely represent a clinical correlate for the formation of Retinal Telangiectasia or Coats-like vasculopathy in patients with CRB1 mutations that are thought to depend on such genetic modifiers.
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The severity of Retinal pathology in homozygous Crb1rd8/rd8 mice is dependent on additional genetic factors
Human molecular genetics, 2014Co-Authors: Ulrich F. O. Luhmann, Livia S. Carvalho, Sophia-martha Kleine Holthaus, Jill A. Cowing, Simon Greenaway, Colin J Chu, Philipp Herrmann, Alexander J. Smith, Peter M. G. Munro, Paul K. PotterAbstract:Understanding phenotype-genotype correlations in Retinal degeneration is a major challenge. Mutations in CRB1 lead to a spectrum of autosomal recessive Retinal dystrophies with variable phenotypes suggesting the influence of modifying factors. To establish the contribution of the genetic background to phenotypic variability associated with the Crb1(rd8/rd8) mutation, we compared the Retinal pathology of Crb1(rd8/rd8)/J inbred mice with that of two Crb1(rd8/rd8) lines backcrossed with C57BL/6JOlaHsd mice. Topical endoscopic fundal imaging and scanning laser ophthalmoscopy fundus images of all three Crb1(rd8/rd8) lines showed a significant increase in the number of inferior Retinal lesions that was strikingly variable between the lines. Optical coherence tomography, semithin, ultrastructural morphology and assessment of inflammatory and vascular marker by immunohistochemistry and quantitative reverse transcriptase-polymerase chain reaction revealed that the lesions were associated with photoreceptor death, Muller and microglia activation and Telangiectasia-like vascular remodelling-features that were stable in the inbred, variable in the second, but virtually absent in the third Crb1(rd8/rd8) line, even at 12 months of age. This suggests that the Crb1(rd8/rd8) mutation is necessary, but not sufficient for the development of these degenerative features. By whole-genome SNP analysis of the genotype-phenotype correlation, a candidate region on chromosome 15 was identified. This may carry one or more genetic modifiers for the manifestation of the Retinal pathology associated with mutations in Crb1. This study also provides insight into the nature of the Retinal vascular lesions that likely represent a clinical correlate for the formation of Retinal Telangiectasia or Coats-like vasculopathy in patients with CRB1 mutations that are thought to depend on such genetic modifiers.
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Differential Modulation of Retinal Degeneration by Ccl2 and Cx3cr1 Chemokine Signalling
2013Co-Authors: Ulrich F. O. Luhmann, Livia S. Carvalho, Jill A. Cowing, Peter M. G. Munro, Hannah E J Armer, Vy Luong, Robert E. Maclaren, Clemens A. Lange, Scott Robbie, Frederick W. FitzkeAbstract:Microglia and macrophages are recruited to sites of Retinal degeneration where local cytokines and chemokines determine protective or neurotoxic microglia responses. Defining the role of Ccl2-Ccr2 and Cx3cl1-Cx3cr1 signalling for Retinal pathology is of particular interest because of its potential role in age-related macular degeneration (AMD). Ccl2, Ccr2, and Cx3cr1 signalling defects impair macrophage trafficking, but have, in several conflicting studies, been reported to show different degrees of age-related Retinal degeneration. Ccl2/Cx3cr1 double knockout (CCDKO) mice show an early onset Retinal degeneration and have been suggested as a model for AMD. In order to understand phenotypic discrepancies in different chemokine knockout lines and to study how defects in Ccl2 and/or Cx3cr1 signalling contribute to the described early onset Retinal degeneration, we defined primary and secondary pathological events in CCDKO mice. To control for genetic background variability, we compared the original phenotype with that of single Ccl2, Cx3cr1 and Ccl2/Cx3cr1 double knockout mice obtained from backcrosses of CCDKO with C57Bl/6 mice. We found that the primary pathological event in CCDKO mice develops in the inferior outer nuclear layer independently of light around postnatal day P14. RPE and vascular lesions develop secondarily with increasing penetrance with age and are clinically similar to Retinal Telangiectasia not to choroidal neovascularisation. Furthermore, we provide evidence that a third autosomal recessive gene causes the degeneration in CCDKO mice and in all affected re-derived lines and subsequently demonstrated co-segregation of th
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Differential Modulation of Retinal Degeneration by Ccl2 and Cx3cr1 Chemokine Signalling
PloS one, 2012Co-Authors: Ulrich F. O. Luhmann, Livia S. Carvalho, Jill A. Cowing, Peter M. G. Munro, Clemens Lange, Scott J. Robbie, Hannah E J Armer, Vy Luong, Robert E. Maclaren, Frederick W. FitzkeAbstract:Microglia and macrophages are recruited to sites of Retinal degeneration where local cytokines and chemokines determine protective or neurotoxic microglia responses. Defining the role of Ccl2-Ccr2 and Cx3cl1-Cx3cr1 signalling for Retinal pathology is of particular interest because of its potential role in age-related macular degeneration (AMD). Ccl2, Ccr2, and Cx3cr1 signalling defects impair macrophage trafficking, but have, in several conflicting studies, been reported to show different degrees of age-related Retinal degeneration. Ccl2/Cx3cr1 double knockout (CCDKO) mice show an early onset Retinal degeneration and have been suggested as a model for AMD. In order to understand phenotypic discrepancies in different chemokine knockout lines and to study how defects in Ccl2 and/or Cx3cr1 signalling contribute to the described early onset Retinal degeneration, we defined primary and secondary pathological events in CCDKO mice. To control for genetic background variability, we compared the original phenotype with that of single Ccl2, Cx3cr1 and Ccl2/Cx3cr1 double knockout mice obtained from backcrosses of CCDKO with C57Bl/6 mice. We found that the primary pathological event in CCDKO mice develops in the inferior outer nuclear layer independently of light around postnatal day P14. RPE and vascular lesions develop secondarily with increasing penetrance with age and are clinically similar to Retinal Telangiectasia not to choroidal neovascularisation. Furthermore, we provide evidence that a third autosomal recessive gene causes the degeneration in CCDKO mice and in all affected re-derived lines and subsequently demonstrated co-segregation of the naturally occurring RD8 mutation in the Crb1 gene. By comparing CCDKO mice with re-derived CCl2(-/-)/Crb1(Rd8/RD8), Cx3cr1(-/-)/Crb1(Rd8/RD8) and CCl2(-/-)/Cx3cr1(-/-)/Crb1(Rd8/RD8) mice, we observed a differential modulation of the Retinal phenotype by genetic background and both chemokine signalling pathways. These findings indicate that CCDKO mice are not a model of AMD, but a model for an inherited Retinal degeneration that is differentially modulated by Ccl2-Ccr2 and Cx3cl1-Cx3cr1 chemokine signalling.
Livia S. Carvalho - One of the best experts on this subject based on the ideXlab platform.
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the severity of Retinal pathology in homozygous crb1rd8 rd8 mice is dependent on additional genetic factors
Human Molecular Genetics, 2015Co-Authors: Ulrich F. O. Luhmann, Livia S. Carvalho, Sophia-martha Kleine Holthaus, Jill A. Cowing, Simon Greenaway, Colin J Chu, Philipp Herrmann, Alexander J. Smith, Peter M. G. Munro, Paul K. PotterAbstract:Understanding phenotype-genotype correlations in Retinal degeneration is a major challenge. Mutations in CRB1 lead to a spectrum of autosomal recessive Retinal dystrophies with variable phenotypes suggesting the influence of modifying factors. To establish the contribution of the genetic background to phenotypic variability associated with the Crb1(rd8/rd8) mutation, we compared the Retinal pathology of Crb1(rd8/rd8)/J inbred mice with that of two Crb1(rd8/rd8) lines backcrossed with C57BL/6JOlaHsd mice. Topical endoscopic fundal imaging and scanning laser ophthalmoscopy fundus images of all three Crb1(rd8/rd8) lines showed a significant increase in the number of inferior Retinal lesions that was strikingly variable between the lines. Optical coherence tomography, semithin, ultrastructural morphology and assessment of inflammatory and vascular marker by immunohistochemistry and quantitative reverse transcriptase-polymerase chain reaction revealed that the lesions were associated with photoreceptor death, Muller and microglia activation and Telangiectasia-like vascular remodelling-features that were stable in the inbred, variable in the second, but virtually absent in the third Crb1(rd8/rd8) line, even at 12 months of age. This suggests that the Crb1(rd8/rd8) mutation is necessary, but not sufficient for the development of these degenerative features. By whole-genome SNP analysis of the genotype-phenotype correlation, a candidate region on chromosome 15 was identified. This may carry one or more genetic modifiers for the manifestation of the Retinal pathology associated with mutations in Crb1. This study also provides insight into the nature of the Retinal vascular lesions that likely represent a clinical correlate for the formation of Retinal Telangiectasia or Coats-like vasculopathy in patients with CRB1 mutations that are thought to depend on such genetic modifiers.
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The severity of Retinal pathology in homozygous Crb1rd8/rd8 mice is dependent on additional genetic factors
Human molecular genetics, 2014Co-Authors: Ulrich F. O. Luhmann, Livia S. Carvalho, Sophia-martha Kleine Holthaus, Jill A. Cowing, Simon Greenaway, Colin J Chu, Philipp Herrmann, Alexander J. Smith, Peter M. G. Munro, Paul K. PotterAbstract:Understanding phenotype-genotype correlations in Retinal degeneration is a major challenge. Mutations in CRB1 lead to a spectrum of autosomal recessive Retinal dystrophies with variable phenotypes suggesting the influence of modifying factors. To establish the contribution of the genetic background to phenotypic variability associated with the Crb1(rd8/rd8) mutation, we compared the Retinal pathology of Crb1(rd8/rd8)/J inbred mice with that of two Crb1(rd8/rd8) lines backcrossed with C57BL/6JOlaHsd mice. Topical endoscopic fundal imaging and scanning laser ophthalmoscopy fundus images of all three Crb1(rd8/rd8) lines showed a significant increase in the number of inferior Retinal lesions that was strikingly variable between the lines. Optical coherence tomography, semithin, ultrastructural morphology and assessment of inflammatory and vascular marker by immunohistochemistry and quantitative reverse transcriptase-polymerase chain reaction revealed that the lesions were associated with photoreceptor death, Muller and microglia activation and Telangiectasia-like vascular remodelling-features that were stable in the inbred, variable in the second, but virtually absent in the third Crb1(rd8/rd8) line, even at 12 months of age. This suggests that the Crb1(rd8/rd8) mutation is necessary, but not sufficient for the development of these degenerative features. By whole-genome SNP analysis of the genotype-phenotype correlation, a candidate region on chromosome 15 was identified. This may carry one or more genetic modifiers for the manifestation of the Retinal pathology associated with mutations in Crb1. This study also provides insight into the nature of the Retinal vascular lesions that likely represent a clinical correlate for the formation of Retinal Telangiectasia or Coats-like vasculopathy in patients with CRB1 mutations that are thought to depend on such genetic modifiers.
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Differential Modulation of Retinal Degeneration by Ccl2 and Cx3cr1 Chemokine Signalling
2013Co-Authors: Ulrich F. O. Luhmann, Livia S. Carvalho, Jill A. Cowing, Peter M. G. Munro, Hannah E J Armer, Vy Luong, Robert E. Maclaren, Clemens A. Lange, Scott Robbie, Frederick W. FitzkeAbstract:Microglia and macrophages are recruited to sites of Retinal degeneration where local cytokines and chemokines determine protective or neurotoxic microglia responses. Defining the role of Ccl2-Ccr2 and Cx3cl1-Cx3cr1 signalling for Retinal pathology is of particular interest because of its potential role in age-related macular degeneration (AMD). Ccl2, Ccr2, and Cx3cr1 signalling defects impair macrophage trafficking, but have, in several conflicting studies, been reported to show different degrees of age-related Retinal degeneration. Ccl2/Cx3cr1 double knockout (CCDKO) mice show an early onset Retinal degeneration and have been suggested as a model for AMD. In order to understand phenotypic discrepancies in different chemokine knockout lines and to study how defects in Ccl2 and/or Cx3cr1 signalling contribute to the described early onset Retinal degeneration, we defined primary and secondary pathological events in CCDKO mice. To control for genetic background variability, we compared the original phenotype with that of single Ccl2, Cx3cr1 and Ccl2/Cx3cr1 double knockout mice obtained from backcrosses of CCDKO with C57Bl/6 mice. We found that the primary pathological event in CCDKO mice develops in the inferior outer nuclear layer independently of light around postnatal day P14. RPE and vascular lesions develop secondarily with increasing penetrance with age and are clinically similar to Retinal Telangiectasia not to choroidal neovascularisation. Furthermore, we provide evidence that a third autosomal recessive gene causes the degeneration in CCDKO mice and in all affected re-derived lines and subsequently demonstrated co-segregation of th
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Differential Modulation of Retinal Degeneration by Ccl2 and Cx3cr1 Chemokine Signalling
PloS one, 2012Co-Authors: Ulrich F. O. Luhmann, Livia S. Carvalho, Jill A. Cowing, Peter M. G. Munro, Clemens Lange, Scott J. Robbie, Hannah E J Armer, Vy Luong, Robert E. Maclaren, Frederick W. FitzkeAbstract:Microglia and macrophages are recruited to sites of Retinal degeneration where local cytokines and chemokines determine protective or neurotoxic microglia responses. Defining the role of Ccl2-Ccr2 and Cx3cl1-Cx3cr1 signalling for Retinal pathology is of particular interest because of its potential role in age-related macular degeneration (AMD). Ccl2, Ccr2, and Cx3cr1 signalling defects impair macrophage trafficking, but have, in several conflicting studies, been reported to show different degrees of age-related Retinal degeneration. Ccl2/Cx3cr1 double knockout (CCDKO) mice show an early onset Retinal degeneration and have been suggested as a model for AMD. In order to understand phenotypic discrepancies in different chemokine knockout lines and to study how defects in Ccl2 and/or Cx3cr1 signalling contribute to the described early onset Retinal degeneration, we defined primary and secondary pathological events in CCDKO mice. To control for genetic background variability, we compared the original phenotype with that of single Ccl2, Cx3cr1 and Ccl2/Cx3cr1 double knockout mice obtained from backcrosses of CCDKO with C57Bl/6 mice. We found that the primary pathological event in CCDKO mice develops in the inferior outer nuclear layer independently of light around postnatal day P14. RPE and vascular lesions develop secondarily with increasing penetrance with age and are clinically similar to Retinal Telangiectasia not to choroidal neovascularisation. Furthermore, we provide evidence that a third autosomal recessive gene causes the degeneration in CCDKO mice and in all affected re-derived lines and subsequently demonstrated co-segregation of the naturally occurring RD8 mutation in the Crb1 gene. By comparing CCDKO mice with re-derived CCl2(-/-)/Crb1(Rd8/RD8), Cx3cr1(-/-)/Crb1(Rd8/RD8) and CCl2(-/-)/Cx3cr1(-/-)/Crb1(Rd8/RD8) mice, we observed a differential modulation of the Retinal phenotype by genetic background and both chemokine signalling pathways. These findings indicate that CCDKO mice are not a model of AMD, but a model for an inherited Retinal degeneration that is differentially modulated by Ccl2-Ccr2 and Cx3cl1-Cx3cr1 chemokine signalling.
Raja Narayanan - One of the best experts on this subject based on the ideXlab platform.
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diagnosis of subRetinal neovascularization associated with idiopathic juxtafoveal Retinal Telangiectasia fluorescein angiography versus spectral domain optical coherence tomography
Graefes Archive for Clinical and Experimental Ophthalmology, 2014Co-Authors: Jay Chhablani, Kopal Mithal, Harsha Rao, Raja NarayananAbstract:Background To compare ability of fluorescein angiography (FFA) and spectral-domain optical coherence tomography (SD-OCT) to diagnose subRetinal neovascularization (SRNV) secondary to idiopathic juxtafoveal Retinal Telangiectasia (IJRT) type 2A.