The retina is one of the most essential elements of vision pathway in vertebrate. The dysplasia of retina cause congenital blindness or vision disability in individuals, and the misbalance in adult retinal vascular ho...The retina is one of the most essential elements of vision pathway in vertebrate. The dysplasia of retina cause congenital blindness or vision disability in individuals, and the misbalance in adult retinal vascular homeostasis leads to neo adults, such as diabetic retinopathy or age-related macular degeneration. Many developmental signaling pathways are involved in the process of retinal development and vascular homeostasis. Among them, Notch signaling pathway has long been studied, and Notch signaling-interfered mouse models show both neural retina dysplasia and vascular abnormality. In this review, we discuss the roles of Notch signaling in the maintenance of retinal progenitor cells, specification of retinal neurons and glial cells, and the sustaining of retina vascular homeostasis, especially from the aspects of conditional knockout mouse models. The potential of Notch signal manipulation may provide a powerful cell fate- and neovascularization-controUing tool that could have important applications in treatment of retinal diseases.展开更多
Insulin resistance is a hallmark of type 2 diabetes. In an effort to understand and treat this condition, re searchers have used genetic manipulation of mice to uncover insulin signaling pathways and determine the eff...Insulin resistance is a hallmark of type 2 diabetes. In an effort to understand and treat this condition, re searchers have used genetic manipulation of mice to uncover insulin signaling pathways and determine the effects of their perturbation. After decades of research much has been learned, but the pathophysiology o insulin resistance in human diabetes remains contro versial, and treating insulin resistance remains a chal lenge. This review will discuss limitations of mouse models lacking select insulin signaling molecule genes In the most influential mouse models, glucose metabo lism differs from that of humans at the cellular, organ and whole-organism levels, and these differences limi the relevance and benefit of the mouse models both in terms of mechanistic investigations and therapeutic development. These differences are due partly to im mutable differences in mouse and human biology, and partly to the failure of genetic modifications to produce an accurate model of human diabetes. Several fac tors often limit the mechanistic insights gained from experimental mice to the particular species and strain including: developmental effects, unexpected meta bolic adjustments, genetic background effects, and technical issues. We conclude that the limitations and weaknesses of genetically modified mouse models of insulin resistance underscore the need for redirection of research efforts toward methods that are more directly relevant to human physiology.展开更多
Increasing evidence suggests that a complex net-work of fever induction pathways in mammalian exists. In this article,the overview of recent studies on the mechanism of fever induced by different pyrogens using IL-1, ...Increasing evidence suggests that a complex net-work of fever induction pathways in mammalian exists. In this article,the overview of recent studies on the mechanism of fever induced by different pyrogens using IL-1, IL-1R, ICE, IL-1ra, IL-1RacP, IL-6,IL-10,TNFR,cPLA 2,COX,EP,AT 2,iNOS and D 2/3 knockout mice is presented. Hyperthermia respond to localized infection/inflammation(e.g.,sc injection of turpentine) is mediated by IL-1β and IL-6 in turn.While fever induced by systemic infection/inflammation(e.g.,treatment with LPS intraperitoneally) varies with the different doses of pyrogens administered .Fever caused by a low dose of LPS administered ip is IL-6 dependent ,but the IL-6 independent pathway is crucial for the fever evoked by a high dose of LPS.Febrile responses during both local and systemic infection/inflammation develop totally through central PGE 2 dependent mechanism, but some stress induced hyperthermia otherwise.展开更多
Disorders of sex development often arise from anomalies in the molecular or cellular networks that guide the differentiation of the embryonic gonad into either a testis or an ovary, two functionally distinct organs. T...Disorders of sex development often arise from anomalies in the molecular or cellular networks that guide the differentiation of the embryonic gonad into either a testis or an ovary, two functionally distinct organs. The activation of the Y-linked gene Sry （sex- determining region Y） and its downstream target Sox9 （Sry box-containing gene 9） triggers testis differentiation by stimulating the differentiation of Sertoli cells, which then direct testis morphogenesis. Once engaged, a genetic pathway promotes the testis development while actively suppressing genes involved in ovarian development. This review focuses on the events of testis determination and the struggle to maintain male fate in the face of antagonistic pressure from the underlying female programme.展开更多
Survival of children with chronic medical illnesses is leading to an increase in secondary osteoporosis due to impaired peak bone mass （PBM）. Insulin-like growth factor type Ⅰ （IGF-1） levels correlate with the pa...Survival of children with chronic medical illnesses is leading to an increase in secondary osteoporosis due to impaired peak bone mass （PBM）. Insulin-like growth factor type Ⅰ （IGF-1） levels correlate with the pattern of bone mass accrual and many chronic illnesses are associated with low IGF-1 levels. Reduced serum levels of IGF-1 minimally affect the integrity of the skeleton, whereas recent studies suggest that skeletal IGF-I regulates PBM. To determine the role of IGF-1 in postnatal bone mass accrual regardless of source, we established an inducible type 1 Igf receptor Cre/lox knockout mouse model, in which the type 1 Igf receptor was deleted inducibely in the mesenchymal stem cells （MSCs） from 3-7 weeks of age. The size of the mouse was not affected as knockout and wild type mice had similar body weights and nasoanal and femoral lengths. However, bone volume and trabecular bone thickness were decreased in the secondary spongiosa of female knockout mice relative to wild type controls, indicating that IGF-1 is critical for bone mass. IGF-1 signaling in MSCs in vitro has been implicated to be involved in both migration to the bone surface and differentiation into bone forming osteoblasts. To clarify the exact role of IGF-1 in bone, we found by immunohistochemical analysis that a similar number of Osterix-positive osteoprogenitors were on the bone perimeter, indicating migration of MSCs was not affected. Most importantly, 56% fewer osteocalcin-positive mature osteoblasts were present on the bone perimeter in the secondary spongiosa in knockout mice versus wild type littermates. These in vivo data demonstrate that the primary role of skeletal IGF-1 is for the terminal differentiation of osteoprogenitors, but refute the role of IGF-1 in MSC migration in vivo. Additionally, these findings confirm that impaired IGF-1 signaling in bone MSCs is sufficient to impair bone mass acquisition.展开更多
CD146 is a newly identified endothelial biomarker that has been implicated in angiogenesis. Though in vitro angio- genic function of CD146 has been extensively reported, in vivo evidence is still lacking. To address t...CD146 is a newly identified endothelial biomarker that has been implicated in angiogenesis. Though in vitro angio- genic function of CD146 has been extensively reported, in vivo evidence is still lacking. To address this issue, we generated endothelial-specific CD146 knockout （CD146 EC-Ko） mice using the Tg（Tek-cre） system. Surprisingly, these mice did not exhibit any apparent morphological defects in the development of normal retinal vasculature. To evaluate the role of CD146 in pathological angiogenesis, a xenograft tumor model was used. We found that both tumor volume and vascular density were significantly lower in CD146Ec-KO mice when compared to WT littermates. Additionally, the ability for sprouting, migration and tube formation in response to VEGF treatment was impaired in endothelial cells （ECs）of CD146Ec-Ko mice. Mechanistic studies further confirmed that VEGF- induced VEGFR-2 phosphorylation and AKT/p38 MAPKs/ NF-KB activation were inhibited in these CD146-null ECs, which might present the underlying cause for the observed inhibition of tumor angiogenesis in CD146Ec-Ko mice. These results suggest that CD146 plays a redundant role in physiological angiogenic processes, but becomes essential during pathological angiogenesis as observed in tumorigenesis.展开更多
基金supported by the grants from the Natural Science Foundation of China (Nos.30770693 and 30830067)the Ministry of Science and Technology of China (No. 2009CB521706)
文摘The retina is one of the most essential elements of vision pathway in vertebrate. The dysplasia of retina cause congenital blindness or vision disability in individuals, and the misbalance in adult retinal vascular homeostasis leads to neo adults, such as diabetic retinopathy or age-related macular degeneration. Many developmental signaling pathways are involved in the process of retinal development and vascular homeostasis. Among them, Notch signaling pathway has long been studied, and Notch signaling-interfered mouse models show both neural retina dysplasia and vascular abnormality. In this review, we discuss the roles of Notch signaling in the maintenance of retinal progenitor cells, specification of retinal neurons and glial cells, and the sustaining of retina vascular homeostasis, especially from the aspects of conditional knockout mouse models. The potential of Notch signal manipulation may provide a powerful cell fate- and neovascularization-controUing tool that could have important applications in treatment of retinal diseases.
文摘Insulin resistance is a hallmark of type 2 diabetes. In an effort to understand and treat this condition, re searchers have used genetic manipulation of mice to uncover insulin signaling pathways and determine the effects of their perturbation. After decades of research much has been learned, but the pathophysiology o insulin resistance in human diabetes remains contro versial, and treating insulin resistance remains a chal lenge. This review will discuss limitations of mouse models lacking select insulin signaling molecule genes In the most influential mouse models, glucose metabo lism differs from that of humans at the cellular, organ and whole-organism levels, and these differences limi the relevance and benefit of the mouse models both in terms of mechanistic investigations and therapeutic development. These differences are due partly to im mutable differences in mouse and human biology, and partly to the failure of genetic modifications to produce an accurate model of human diabetes. Several fac tors often limit the mechanistic insights gained from experimental mice to the particular species and strain including: developmental effects, unexpected meta bolic adjustments, genetic background effects, and technical issues. We conclude that the limitations and weaknesses of genetically modified mouse models of insulin resistance underscore the need for redirection of research efforts toward methods that are more directly relevant to human physiology.
文摘Increasing evidence suggests that a complex net-work of fever induction pathways in mammalian exists. In this article,the overview of recent studies on the mechanism of fever induced by different pyrogens using IL-1, IL-1R, ICE, IL-1ra, IL-1RacP, IL-6,IL-10,TNFR,cPLA 2,COX,EP,AT 2,iNOS and D 2/3 knockout mice is presented. Hyperthermia respond to localized infection/inflammation(e.g.,sc injection of turpentine) is mediated by IL-1β and IL-6 in turn.While fever induced by systemic infection/inflammation(e.g.,treatment with LPS intraperitoneally) varies with the different doses of pyrogens administered .Fever caused by a low dose of LPS administered ip is IL-6 dependent ,but the IL-6 independent pathway is crucial for the fever evoked by a high dose of LPS.Febrile responses during both local and systemic infection/inflammation develop totally through central PGE 2 dependent mechanism, but some stress induced hyperthermia otherwise.
文摘Disorders of sex development often arise from anomalies in the molecular or cellular networks that guide the differentiation of the embryonic gonad into either a testis or an ovary, two functionally distinct organs. The activation of the Y-linked gene Sry （sex- determining region Y） and its downstream target Sox9 （Sry box-containing gene 9） triggers testis differentiation by stimulating the differentiation of Sertoli cells, which then direct testis morphogenesis. Once engaged, a genetic pathway promotes the testis development while actively suppressing genes involved in ovarian development. This review focuses on the events of testis determination and the struggle to maintain male fate in the face of antagonistic pressure from the underlying female programme.
基金supported in part by the grants from the United States National Institute of Health NIDDK including T32DK07751 (JLC)the Diabetes Research and Training Center grant P60DK079637(JSF),and DK057501 and DK08098 (XC)
文摘Survival of children with chronic medical illnesses is leading to an increase in secondary osteoporosis due to impaired peak bone mass （PBM）. Insulin-like growth factor type Ⅰ （IGF-1） levels correlate with the pattern of bone mass accrual and many chronic illnesses are associated with low IGF-1 levels. Reduced serum levels of IGF-1 minimally affect the integrity of the skeleton, whereas recent studies suggest that skeletal IGF-I regulates PBM. To determine the role of IGF-1 in postnatal bone mass accrual regardless of source, we established an inducible type 1 Igf receptor Cre/lox knockout mouse model, in which the type 1 Igf receptor was deleted inducibely in the mesenchymal stem cells （MSCs） from 3-7 weeks of age. The size of the mouse was not affected as knockout and wild type mice had similar body weights and nasoanal and femoral lengths. However, bone volume and trabecular bone thickness were decreased in the secondary spongiosa of female knockout mice relative to wild type controls, indicating that IGF-1 is critical for bone mass. IGF-1 signaling in MSCs in vitro has been implicated to be involved in both migration to the bone surface and differentiation into bone forming osteoblasts. To clarify the exact role of IGF-1 in bone, we found by immunohistochemical analysis that a similar number of Osterix-positive osteoprogenitors were on the bone perimeter, indicating migration of MSCs was not affected. Most importantly, 56% fewer osteocalcin-positive mature osteoblasts were present on the bone perimeter in the secondary spongiosa in knockout mice versus wild type littermates. These in vivo data demonstrate that the primary role of skeletal IGF-1 is for the terminal differentiation of osteoprogenitors, but refute the role of IGF-1 in MSC migration in vivo. Additionally, these findings confirm that impaired IGF-1 signaling in bone MSCs is sufficient to impair bone mass acquisition.
文摘CD146 is a newly identified endothelial biomarker that has been implicated in angiogenesis. Though in vitro angio- genic function of CD146 has been extensively reported, in vivo evidence is still lacking. To address this issue, we generated endothelial-specific CD146 knockout （CD146 EC-Ko） mice using the Tg（Tek-cre） system. Surprisingly, these mice did not exhibit any apparent morphological defects in the development of normal retinal vasculature. To evaluate the role of CD146 in pathological angiogenesis, a xenograft tumor model was used. We found that both tumor volume and vascular density were significantly lower in CD146Ec-KO mice when compared to WT littermates. Additionally, the ability for sprouting, migration and tube formation in response to VEGF treatment was impaired in endothelial cells （ECs）of CD146Ec-Ko mice. Mechanistic studies further confirmed that VEGF- induced VEGFR-2 phosphorylation and AKT/p38 MAPKs/ NF-KB activation were inhibited in these CD146-null ECs, which might present the underlying cause for the observed inhibition of tumor angiogenesis in CD146Ec-Ko mice. These results suggest that CD146 plays a redundant role in physiological angiogenic processes, but becomes essential during pathological angiogenesis as observed in tumorigenesis.
