The Experts below are selected from a list of 318 Experts worldwide ranked by ideXlab platform
Dean J. Burkin - One of the best experts on this subject based on the ideXlab platform.
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Human laminin-111 and laminin-211 protein therapy prevents Muscle Disease progression in an immunodeficient mouse model of LAMA2-CMD.
Skeletal muscle, 2020Co-Authors: Pamela Barraza-flores, Hailey J. Hermann, Christina R. Bates, Tyler G. Allen, Timothy T. Grunert, Dean J. BurkinAbstract:Laminin-α2-related congenital muscular dystrophy (LAMA2-CMD) is a devastating genetic Disease caused by mutations in the LAMA2 gene. These mutations result in progressive Muscle wasting and inflammation leading to delayed milestones, and reduced lifespan in affected patients. There is currently no cure or treatment for LAMA2-CMD. Preclinical studies have demonstrated that mouse laminin-111 can serve as an effective protein replacement therapy in a mouse model of LAMA2-CMD. In this study, we generated a novel immunocompromised dyW mouse model of LAMA2-CMD to study the role the immune system plays in Muscle Disease progression. We used this immune-deficient dyW mouse model to test the therapeutic benefits of recombinant human laminin-111 and laminin-211 protein therapy on laminin-α2-deficient Muscle Disease progression. We show that immunodeficient laminin-α2 null mice demonstrate subtle differences in Muscle regeneration compared to immunocompetent animals during early Disease stages but overall exhibit a comparable Muscle Disease progression. We found human laminin-111 and laminin-211 could serve as effective protein replacement strategies with mice showing improvements in Muscle pathology and function. We observed that human laminin-111 and laminin-211 exhibit differences on satellite and myoblast cell populations and differentially affect Muscle repair. This study describes the generation of a novel immunodeficient mouse model that allows investigation of the role the immune system plays in LAMA2-CMD. This model can be used to assess the therapeutic potential of heterologous therapies that would elicit an immune response. Using this model, we show that recombinant human laminin-111 can serve as effective protein replacement therapy for the treatment of LAMA2-CMD.
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Laminin-111 protein therapy after Disease onset slows Muscle Disease in a mouse model of laminin-α2 related congenital muscular dystrophy.
Human molecular genetics, 2020Co-Authors: Pamela Barraza-flores, Katherine E. Bukovec, Marisela Dagda, Brandon W Conner, Ariany Oliveira-santos, Robert W. Grange, Dean J. BurkinAbstract:Laminin-α2 related congenital muscular dystrophy (LAMA2-CMD) is a fatal Muscle Disease caused by mutations in the LAMA2 gene. Laminin-α2 is critical for the formation of laminin-211 and -221 heterotrimers in the Muscle basal lamina. LAMA2-CMD patients exhibit hypotonia from birth and progressive Muscle loss that results in developmental delay, confinement to a wheelchair, respiratory insufficiency and premature death. There is currently no cure or effective treatment for LAMA2-CMD. Several studies have shown laminin-111 can serve as an effective protein-replacement therapy for LAMA2-CMD. Studies have demonstrated early treatment with laminin-111 protein results in an increase in life expectancy and improvements in Muscle pathology and function. Since LAMA2-CMD patients are often diagnosed after advanced Disease, it is unclear if laminin-111 protein therapy at an advanced stage of the Disease can have beneficial outcomes. In this study, we tested the efficacy of laminin-111 protein therapy after Disease onset in a mouse model of LAMA2-CMD. Our results showed laminin-111 treatment after Muscle Disease onset increased life expectancy, promoted Muscle growth and increased Muscle stiffness. Together these studies indicate laminin-111 protein therapy either early or late in the Disease process could serve as an effective protein replacement therapy for LAMA2-CMD.
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Human Laminin-111 and Laminin-211 protein therapy prevents Muscle Disease progression in an immune deficient mouse model of LAMA2-CMD
2020Co-Authors: Pamela Barraza-flores, Hailey J. Hermann, Christina R. Bates, Tyler G. Allen, Timothy T. Grunert, Dean J. BurkinAbstract:Abstract Background Laminin-α2 related Congenital Muscular dystrophy (LAMA2-CMD) is a devastating genetic Disease caused by mutations in the LAMA2 gene. These mutations result in progressive Muscle wasting and inflammation leading to delayed milestones, and reduced lifespan in affected patients. There is currently no cure or treatment for LAMA2-CMD. Preclinical studies have demonstrated that mouse Laminin-111 can serve as an effective protein replacement therapy in a mouse model of LAMA2-CMD. Methods In this study, we generated a novel immunocompromised dy W mouse model of LAMA2-CMD to study the role the immune system plays in Muscle Disease progression. We used this immune deficient dy W mouse model to test the therapeutic benefits of recombinant human laminin-111 and laminin-211 protein therapy on Laminin-α2 deficient Muscle Disease progression. Results We show that immune deficient Laminin-α2 null mice demonstrate subtle differences in Muscle regeneration compared to immune competent animals during early Disease stages, but overall exhibit a comparable Muscle Disease progression. We found human laminin-111 and laminin-211 could serve as effective protein replacement strategies with mice showing improvements in Muscle pathology and function. We observed that human laminin-111 and laminin-211 exhibit differences on satellite and myoblast cell populations and differentially affect Muscle repair. Conclusions This study describes the generation of a novel immune deficient mouse model that allows investigation of the role the immune system plays in LAMA2-CMD. This model can be used to assess the therapeutic potential of heterologous therapies that would illicit an immune response. Using this model, we show that recombinant human Laminin-111 can serve as effective protein replacement therapy for the treatment of LAMA2-CMD.
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laminin 111 protein therapy prevents Muscle Disease in the mdx mouse model for duchenne muscular dystrophy
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Jachinta E. Rooney, Praveen B. Gurpur, Dean J. BurkinAbstract:Duchenne muscular dystrophy (DMD) is a devastating neuromuscular Disease caused by mutations in the gene encoding dystrophin. Loss of dystrophin results in reduced sarcolemmal integrity and increased susceptibility to Muscle damage. The α7β1-integrin is a laminin-binding protein up-regulated in the skeletal Muscle of DMD patients and in the mdx mouse model. Transgenic overexpression of the α7-integrin alleviates Muscle Disease in dystrophic mice, making this gene a target for pharmacological intervention. Studies suggest laminin may regulate α7-integrin expression. To test this hypothesis, mouse and human myoblasts were treated with laminin and assayed for α7-integrin expression. We show that laminin-111 (α1, β1, γ1), which is expressed during embryonic development but absent in normal or dystrophic skeletal Muscle, increased α7-integrin expression in mouse and DMD patient myoblasts. Injection of laminin-111 protein into the mdx mouse model of DMD increased expression of α7-integrin, stabilized the sarcolemma, restored serum creatine kinase to wild-type levels, and protected Muscle from exercised-induced damage. These findings demonstrate that laminin-111 is a highly potent therapeutic agent for the mdx mouse model of DMD and represents a paradigm for the systemic delivery of extracellular matrix proteins as therapies for genetic Diseases.
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Laminin-111 protein therapy prevents Muscle Disease in the mdx mouse model for Duchenne muscular dystrophy
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Jachinta E. Rooney, Praveen B. Gurpur, Dean J. BurkinAbstract:Duchenne muscular dystrophy (DMD) is a devastating neuromuscular Disease caused by mutations in the gene encoding dystrophin. Loss of dystrophin results in reduced sarcolemmal integrity and increased susceptibility to Muscle damage. The alpha(7)beta(1)-integrin is a laminin-binding protein up-regulated in the skeletal Muscle of DMD patients and in the mdx mouse model. Transgenic overexpression of the alpha(7)-integrin alleviates Muscle Disease in dystrophic mice, making this gene a target for pharmacological intervention. Studies suggest laminin may regulate alpha(7)-integrin expression. To test this hypothesis, mouse and human myoblasts were treated with laminin and assayed for alpha(7)-integrin expression. We show that laminin-111 (alpha(1), beta(1), gamma(1)), which is expressed during embryonic development but absent in normal or dystrophic skeletal Muscle, increased alpha(7)-integrin expression in mouse and DMD patient myoblasts. Injection of laminin-111 protein into the mdx mouse model of DMD increased expression of alpha(7)-integrin, stabilized the sarcolemma, restored serum creatine kinase to wild-type levels, and protected Muscle from exercised-induced damage. These findings demonstrate that laminin-111 is a highly potent therapeutic agent for the mdx mouse model of DMD and represents a paradigm for the systemic delivery of extracellular matrix proteins as therapies for genetic Diseases.
Eugene J Wyatt - One of the best experts on this subject based on the ideXlab platform.
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direct reprogramming of urine derived cells with inducible myod for modeling human Muscle Disease
Skeletal Muscle, 2016Co-Authors: Ellis Y Kim, Elizabeth M. Mcnally, Patrick G T Page, Lisa Dellefavecastillo, Eugene J WyattAbstract:Cellular models of Muscle Disease are taking on increasing importance with the large number of genes and mutations implicated in causing myopathies and the concomitant need to test personalized therapies. Developing cell models relies on having an easily obtained source of cells, and if the cells are not derived from Muscle itself, a robust reprogramming process is needed. Fibroblasts are a human cell source that works well for the generation of induced pluripotent stem cells, which can then be differentiated into cardiomyocyte lineages, and with less efficiency, skeletal Muscle-like lineages. Alternatively, direct reprogramming with the transcription factor MyoD has been used to generate myotubes from cultured human fibroblasts. Although useful, fibroblasts require a skin biopsy to obtain and this can limit their access, especially from pediatric populations. We now demonstrate that direct reprogramming of urine-derived cells is a highly efficient and reproducible process that can be used to establish human myogenic cells. We show that this method can be applied to urine cells derived from normal individuals as well as those with Muscle Diseases. Furthermore, we show that urine-derived cells can be edited using CRISPR/Cas9 technology. With progress in understanding the molecular etiology of human Muscle Diseases, having a readily available, noninvasive source of cells from which to generate Muscle-like cells is highly useful.
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Direct reprogramming of urine-derived cells with inducible MyoD for modeling human Muscle Disease
Skeletal Muscle, 2016Co-Authors: Ellis Y Kim, Elizabeth M. Mcnally, Patrick Page, Lisa M. Dellefave-castillo, Eugene J WyattAbstract:Background Cellular models of Muscle Disease are taking on increasing importance with the large number of genes and mutations implicated in causing myopathies and the concomitant need to test personalized therapies. Developing cell models relies on having an easily obtained source of cells, and if the cells are not derived from Muscle itself, a robust reprogramming process is needed. Fibroblasts are a human cell source that works well for the generation of induced pluripotent stem cells, which can then be differentiated into cardiomyocyte lineages, and with less efficiency, skeletal Muscle-like lineages. Alternatively, direct reprogramming with the transcription factor MyoD has been used to generate myotubes from cultured human fibroblasts. Although useful, fibroblasts require a skin biopsy to obtain and this can limit their access, especially from pediatric populations. Results We now demonstrate that direct reprogramming of urine-derived cells is a highly efficient and reproducible process that can be used to establish human myogenic cells. We show that this method can be applied to urine cells derived from normal individuals as well as those with Muscle Diseases. Furthermore, we show that urine-derived cells can be edited using CRISPR/Cas9 technology. Conclusions With progress in understanding the molecular etiology of human Muscle Diseases, having a readily available, noninvasive source of cells from which to generate Muscle-like cells is highly useful.
Ellis Y Kim - One of the best experts on this subject based on the ideXlab platform.
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direct reprogramming of urine derived cells with inducible myod for modeling human Muscle Disease
Skeletal Muscle, 2016Co-Authors: Ellis Y Kim, Elizabeth M. Mcnally, Patrick G T Page, Lisa Dellefavecastillo, Eugene J WyattAbstract:Cellular models of Muscle Disease are taking on increasing importance with the large number of genes and mutations implicated in causing myopathies and the concomitant need to test personalized therapies. Developing cell models relies on having an easily obtained source of cells, and if the cells are not derived from Muscle itself, a robust reprogramming process is needed. Fibroblasts are a human cell source that works well for the generation of induced pluripotent stem cells, which can then be differentiated into cardiomyocyte lineages, and with less efficiency, skeletal Muscle-like lineages. Alternatively, direct reprogramming with the transcription factor MyoD has been used to generate myotubes from cultured human fibroblasts. Although useful, fibroblasts require a skin biopsy to obtain and this can limit their access, especially from pediatric populations. We now demonstrate that direct reprogramming of urine-derived cells is a highly efficient and reproducible process that can be used to establish human myogenic cells. We show that this method can be applied to urine cells derived from normal individuals as well as those with Muscle Diseases. Furthermore, we show that urine-derived cells can be edited using CRISPR/Cas9 technology. With progress in understanding the molecular etiology of human Muscle Diseases, having a readily available, noninvasive source of cells from which to generate Muscle-like cells is highly useful.
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Direct reprogramming of urine-derived cells with inducible MyoD for modeling human Muscle Disease
Skeletal Muscle, 2016Co-Authors: Ellis Y Kim, Elizabeth M. Mcnally, Patrick Page, Lisa M. Dellefave-castillo, Eugene J WyattAbstract:Background Cellular models of Muscle Disease are taking on increasing importance with the large number of genes and mutations implicated in causing myopathies and the concomitant need to test personalized therapies. Developing cell models relies on having an easily obtained source of cells, and if the cells are not derived from Muscle itself, a robust reprogramming process is needed. Fibroblasts are a human cell source that works well for the generation of induced pluripotent stem cells, which can then be differentiated into cardiomyocyte lineages, and with less efficiency, skeletal Muscle-like lineages. Alternatively, direct reprogramming with the transcription factor MyoD has been used to generate myotubes from cultured human fibroblasts. Although useful, fibroblasts require a skin biopsy to obtain and this can limit their access, especially from pediatric populations. Results We now demonstrate that direct reprogramming of urine-derived cells is a highly efficient and reproducible process that can be used to establish human myogenic cells. We show that this method can be applied to urine cells derived from normal individuals as well as those with Muscle Diseases. Furthermore, we show that urine-derived cells can be edited using CRISPR/Cas9 technology. Conclusions With progress in understanding the molecular etiology of human Muscle Diseases, having a readily available, noninvasive source of cells from which to generate Muscle-like cells is highly useful.
Elizabeth M. Mcnally - One of the best experts on this subject based on the ideXlab platform.
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Direct reprogramming of urine-derived cells with inducible MyoD for modeling human Muscle Disease
Skeletal Muscle, 2016Co-Authors: Ellis Y Kim, Elizabeth M. Mcnally, Patrick Page, Lisa M. Dellefave-castillo, Eugene J WyattAbstract:Background Cellular models of Muscle Disease are taking on increasing importance with the large number of genes and mutations implicated in causing myopathies and the concomitant need to test personalized therapies. Developing cell models relies on having an easily obtained source of cells, and if the cells are not derived from Muscle itself, a robust reprogramming process is needed. Fibroblasts are a human cell source that works well for the generation of induced pluripotent stem cells, which can then be differentiated into cardiomyocyte lineages, and with less efficiency, skeletal Muscle-like lineages. Alternatively, direct reprogramming with the transcription factor MyoD has been used to generate myotubes from cultured human fibroblasts. Although useful, fibroblasts require a skin biopsy to obtain and this can limit their access, especially from pediatric populations. Results We now demonstrate that direct reprogramming of urine-derived cells is a highly efficient and reproducible process that can be used to establish human myogenic cells. We show that this method can be applied to urine cells derived from normal individuals as well as those with Muscle Diseases. Furthermore, we show that urine-derived cells can be edited using CRISPR/Cas9 technology. Conclusions With progress in understanding the molecular etiology of human Muscle Diseases, having a readily available, noninvasive source of cells from which to generate Muscle-like cells is highly useful.
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direct reprogramming of urine derived cells with inducible myod for modeling human Muscle Disease
Skeletal Muscle, 2016Co-Authors: Ellis Y Kim, Elizabeth M. Mcnally, Patrick G T Page, Lisa Dellefavecastillo, Eugene J WyattAbstract:Cellular models of Muscle Disease are taking on increasing importance with the large number of genes and mutations implicated in causing myopathies and the concomitant need to test personalized therapies. Developing cell models relies on having an easily obtained source of cells, and if the cells are not derived from Muscle itself, a robust reprogramming process is needed. Fibroblasts are a human cell source that works well for the generation of induced pluripotent stem cells, which can then be differentiated into cardiomyocyte lineages, and with less efficiency, skeletal Muscle-like lineages. Alternatively, direct reprogramming with the transcription factor MyoD has been used to generate myotubes from cultured human fibroblasts. Although useful, fibroblasts require a skin biopsy to obtain and this can limit their access, especially from pediatric populations. We now demonstrate that direct reprogramming of urine-derived cells is a highly efficient and reproducible process that can be used to establish human myogenic cells. We show that this method can be applied to urine cells derived from normal individuals as well as those with Muscle Diseases. Furthermore, we show that urine-derived cells can be edited using CRISPR/Cas9 technology. With progress in understanding the molecular etiology of human Muscle Diseases, having a readily available, noninvasive source of cells from which to generate Muscle-like cells is highly useful.
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Cardiomyopathy is independent of skeletal Muscle Disease in muscular dystrophy
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2002Co-Authors: Xiaolei Zhu, Michele Hadhazy, Matthew T. Wheeler, Man Yee J Lam, Elizabeth M. McnallyAbstract:Dystrophin and its associated proteins, the sarcoglycans, are normally expressed in heart and skeletal Muscle. Mutations that alter the expression of these membrane-associated proteins lead to muscular dystrophy (MD) and cardiomyopathy in humans. Because of the timing and nature of the accompanying cardiomyopathy, it has been suggested that cardiomyopathy develops as a secondary consequence of skeletal Muscle dysfunction in the muscular dystrophies. To determine whether skeletal Muscle dystrophy contributes to the development of sarcoglycan-mediated cardiomyopathy, we used mice lacking gamma-sarcoglycan and inserted a transgene that "rescued" gamma-sarcoglycan expression only in skeletal Muscle. Gamma-sarcoglycan was expressed in skeletal Muscle under the control of the skeletal Muscle-specific myosin light chain 1/3 promoter. Gamma-sarcoglycan-null mice expressing this transgene fully restore gamma-sarcoglycan expression. Furthermore, the transgene-rescued mice lack the focal necrosis and membrane permeability defects that are a hallmark of MD. Despite correction of the skeletal Muscle Disease, focal degeneration and membrane permeability abnormalities persisted in cardiac Muscle, and notably persisted in the right ventricle. Therefore, heart and skeletal Muscle defects are independent processes in sarcoglycan-mediated muscular dystrophies and, as such, therapy should target both skeletal and cardiac Muscle correction to prevent sudden death due to cardiomyopathy in the muscular dystrophies.
Jachinta E. Rooney - One of the best experts on this subject based on the ideXlab platform.
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laminin 111 protein therapy prevents Muscle Disease in the mdx mouse model for duchenne muscular dystrophy
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Jachinta E. Rooney, Praveen B. Gurpur, Dean J. BurkinAbstract:Duchenne muscular dystrophy (DMD) is a devastating neuromuscular Disease caused by mutations in the gene encoding dystrophin. Loss of dystrophin results in reduced sarcolemmal integrity and increased susceptibility to Muscle damage. The α7β1-integrin is a laminin-binding protein up-regulated in the skeletal Muscle of DMD patients and in the mdx mouse model. Transgenic overexpression of the α7-integrin alleviates Muscle Disease in dystrophic mice, making this gene a target for pharmacological intervention. Studies suggest laminin may regulate α7-integrin expression. To test this hypothesis, mouse and human myoblasts were treated with laminin and assayed for α7-integrin expression. We show that laminin-111 (α1, β1, γ1), which is expressed during embryonic development but absent in normal or dystrophic skeletal Muscle, increased α7-integrin expression in mouse and DMD patient myoblasts. Injection of laminin-111 protein into the mdx mouse model of DMD increased expression of α7-integrin, stabilized the sarcolemma, restored serum creatine kinase to wild-type levels, and protected Muscle from exercised-induced damage. These findings demonstrate that laminin-111 is a highly potent therapeutic agent for the mdx mouse model of DMD and represents a paradigm for the systemic delivery of extracellular matrix proteins as therapies for genetic Diseases.
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Laminin-111 protein therapy prevents Muscle Disease in the mdx mouse model for Duchenne muscular dystrophy
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Jachinta E. Rooney, Praveen B. Gurpur, Dean J. BurkinAbstract:Duchenne muscular dystrophy (DMD) is a devastating neuromuscular Disease caused by mutations in the gene encoding dystrophin. Loss of dystrophin results in reduced sarcolemmal integrity and increased susceptibility to Muscle damage. The alpha(7)beta(1)-integrin is a laminin-binding protein up-regulated in the skeletal Muscle of DMD patients and in the mdx mouse model. Transgenic overexpression of the alpha(7)-integrin alleviates Muscle Disease in dystrophic mice, making this gene a target for pharmacological intervention. Studies suggest laminin may regulate alpha(7)-integrin expression. To test this hypothesis, mouse and human myoblasts were treated with laminin and assayed for alpha(7)-integrin expression. We show that laminin-111 (alpha(1), beta(1), gamma(1)), which is expressed during embryonic development but absent in normal or dystrophic skeletal Muscle, increased alpha(7)-integrin expression in mouse and DMD patient myoblasts. Injection of laminin-111 protein into the mdx mouse model of DMD increased expression of alpha(7)-integrin, stabilized the sarcolemma, restored serum creatine kinase to wild-type levels, and protected Muscle from exercised-induced damage. These findings demonstrate that laminin-111 is a highly potent therapeutic agent for the mdx mouse model of DMD and represents a paradigm for the systemic delivery of extracellular matrix proteins as therapies for genetic Diseases.
