In previous research, chimerical BPI23-Fcy1 gene which consisted of human bactericidal/permeability increasing protein （BPI） gene of encoding the functional N terminus （amino acid residues 1 to 199） of human BPI a...In previous research, chimerical BPI23-Fcy1 gene which consisted of human bactericidal/permeability increasing protein （BPI） gene of encoding the functional N terminus （amino acid residues 1 to 199） of human BPI and Fcy1 gene of encoding the Fc segment of human immunoglobulin G1 was successfully reconstructed within a recombinant adeno-associated virus serotype 2 （rAAV2） vector as rAAV2-BPI23-Fcy1. Here, to evaluate the potentiality of applying gene therapy to gram negative bacterial （GNB） infection in high-risk patients, we investigated protection of immuno-compromised mice and immunocompetent mice from challenge with minimal lethal dose （MLD） Klebsiella pneumonia infection after rAAV2-BPI23-Fcy1 gene transferred. The results showed that the survival rate of rAAV2-BPI23-Fcy1 transferred immunocompetent mice as well as immuno-compromised mice （40.0% and 44.4%, respectively） were significant higher than that of corresponding control mice （6.7% and 4.4%, respectively）; the bacteria counting, level of endotoxin and proinflammatory cytokines in the rAAV2-BP123-Fcy1 transferred immuno-compromised mice were markedly lower than that of rAAV2-EGFP and rAAV2-Null transferred immuno- compromised mice. Our data suggest that rAAV2-BPI23-Fcy1 gene transferring offered immuno-compromised mice with resistance against GNB infection, so it is quite potential in preventing GNB infection of clinical high-risk patients. Cellular ＆ Molecular Immunology. 2008;5（6）：439-445.展开更多
Background:Increased catabolism has recently been recognized as a clinical manifestation of amyotrophic lateral sclerosis(ALS).The hypothalamic systems have been shown to be involved in the metabolic dysfunction in AL...Background:Increased catabolism has recently been recognized as a clinical manifestation of amyotrophic lateral sclerosis(ALS).The hypothalamic systems have been shown to be involved in the metabolic dysfunction in ALS,but the exact extent of hypothalamic circuit alterations in ALS is yet to be determined.Here we explored the integrity of large-scale cortico-hypothalamic circuits involved in energy homeostasis in murine models and in ALS patients.Methods:The rAAV2-based large-scale projection mapping and image analysis pipeline based on Wholebrain and Ilastik software suites were used to identify and quantify projections from the forebrain to the lateral hypothalamus in the SOD1(G93A)ALS mouse model(hypermetabolic)and the FusΔNLS ALS mouse model(normo-metabolic).3 T diffusion tensor imaging(DTI)-magnetic resonance imaging(MRI)was performed on 83 ALS and 65 control cases to investigate cortical projections to the lateral hypothalamus(LHA)in ALS.Results:Symptomatic SOD1(G93A)mice displayed an expansion of projections from agranular insula,ventrolateral orbitofrontal and secondary motor cortex to the LHA.These findings were reproduced in an independent cohort by using a different analytic approach.In contrast,in the FusΔNLS ALS mouse model hypothalamic inputs from insula and orbitofrontal cortex were maintained while the projections from motor cortex were lost.The DTI-MRI data confirmed the disruption of the orbitofrontal-hypothalamic tract in ALS patients.Conclusion:This study provides converging murine and human data demonstrating the selective structural disruption of hypothalamic inputs in ALS as a promising factor contributing to the origin of the hypermetabolic phenotype.展开更多
基金funded by the Beijing Municipal Natural Science Foundation (7082016)
文摘In previous research, chimerical BPI23-Fcy1 gene which consisted of human bactericidal/permeability increasing protein （BPI） gene of encoding the functional N terminus （amino acid residues 1 to 199） of human BPI and Fcy1 gene of encoding the Fc segment of human immunoglobulin G1 was successfully reconstructed within a recombinant adeno-associated virus serotype 2 （rAAV2） vector as rAAV2-BPI23-Fcy1. Here, to evaluate the potentiality of applying gene therapy to gram negative bacterial （GNB） infection in high-risk patients, we investigated protection of immuno-compromised mice and immunocompetent mice from challenge with minimal lethal dose （MLD） Klebsiella pneumonia infection after rAAV2-BPI23-Fcy1 gene transferred. The results showed that the survival rate of rAAV2-BPI23-Fcy1 transferred immunocompetent mice as well as immuno-compromised mice （40.0% and 44.4%, respectively） were significant higher than that of corresponding control mice （6.7% and 4.4%, respectively）; the bacteria counting, level of endotoxin and proinflammatory cytokines in the rAAV2-BP123-Fcy1 transferred immuno-compromised mice were markedly lower than that of rAAV2-EGFP and rAAV2-Null transferred immuno- compromised mice. Our data suggest that rAAV2-BPI23-Fcy1 gene transferring offered immuno-compromised mice with resistance against GNB infection, so it is quite potential in preventing GNB infection of clinical high-risk patients. Cellular ＆ Molecular Immunology. 2008;5（6）：439-445.
基金FR is supported by the Thierry Latran Foundation(projects“Trials”and“Hypothals”),the Radala Foundation,the Deutsche Forschungsgemeinschaft(German Research Foundation)-Project-ID 251293561-Collaborative Research Center(CRC)1149 and individual grants 431995586(RO-5004/8-1)and 443642953(RO5004/9-1)the Cellular and Molecular Mechanisms in Aging(CEMMA)Research Training Group,and BMBF(FKZ 01EW1705A,as member of the ERANET-NEURON consortium“MICRONET”)+1 种基金SA and DB are members of the International Graduate School in Molecular Medicine at Ulm UniversityDB is part of the Graduate School in Cellular and Molecular Mechanisms in Aging at Ulm University.Open Access funding enabled and organized by Projekt DEAL.
文摘Background:Increased catabolism has recently been recognized as a clinical manifestation of amyotrophic lateral sclerosis(ALS).The hypothalamic systems have been shown to be involved in the metabolic dysfunction in ALS,but the exact extent of hypothalamic circuit alterations in ALS is yet to be determined.Here we explored the integrity of large-scale cortico-hypothalamic circuits involved in energy homeostasis in murine models and in ALS patients.Methods:The rAAV2-based large-scale projection mapping and image analysis pipeline based on Wholebrain and Ilastik software suites were used to identify and quantify projections from the forebrain to the lateral hypothalamus in the SOD1(G93A)ALS mouse model(hypermetabolic)and the FusΔNLS ALS mouse model(normo-metabolic).3 T diffusion tensor imaging(DTI)-magnetic resonance imaging(MRI)was performed on 83 ALS and 65 control cases to investigate cortical projections to the lateral hypothalamus(LHA)in ALS.Results:Symptomatic SOD1(G93A)mice displayed an expansion of projections from agranular insula,ventrolateral orbitofrontal and secondary motor cortex to the LHA.These findings were reproduced in an independent cohort by using a different analytic approach.In contrast,in the FusΔNLS ALS mouse model hypothalamic inputs from insula and orbitofrontal cortex were maintained while the projections from motor cortex were lost.The DTI-MRI data confirmed the disruption of the orbitofrontal-hypothalamic tract in ALS patients.Conclusion:This study provides converging murine and human data demonstrating the selective structural disruption of hypothalamic inputs in ALS as a promising factor contributing to the origin of the hypermetabolic phenotype.
