Full-body electronic skins for digital meJapan Society for the Promotion of Science:Grants-in-Aid for Scientific ResearchDate (from‐to) : 2022/12 -2029/03 Author : 染谷 隆夫; 松尾 豊; 川原 圭博; 津本 浩平; 岩部 美紀; 横...See More
Full-body electronic skins for digital me
Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
Bringing to light the mechanisms of onset of diet promoted colorectal cancer
Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
Date (from‐to) : 2019/04 -2022/03
Author : Iwabu Miki
Malignant neoplasms or cancers account for 28.5% of all causes of death in Japan; of these, colorectal cancer (CRC) represents not only the third most common cause of death in men but also the most common cause of death in women. While environmental factors, such as diet, are known to have a massive impact on the onset/progression of CRC, the detailed mechanisms involved remain largely unknown. Through analysis of physiologically active substance ISPP1-deficient mice, a newly engineered, as well as through other relevant analyses, this research project has brought to light part of the mechanisms of onset of diet promoted CRC as it is mediated by a decrease in expression and secretion of ISPP1.
Bringing to light the mechanisms of onset of diet promoted colorectal cancerJapan Society for the Promotion of Science:Grants-in-Aid for Scientific ResearchDate (from‐to) : 2019/04 -2022/03 Author : ...See More
Bringing to light the mechanisms of onset of diet promoted colorectal cancer
Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
Date (from‐to) : 2019/04 -2022/03
Author : Iwabu Miki
Malignant neoplasms or cancers account for 28.5% of all causes of death in Japan; of these, colorectal cancer (CRC) represents not only the third most common cause of death in men but also the most common cause of death in women. While environmental factors, such as diet, are known to have a massive impact on the onset/progression of CRC, the detailed mechanisms involved remain largely unknown. Through analysis of physiologically active substance ISPP1-deficient mice, a newly engineered, as well as through other relevant analyses, this research project has brought to light part of the mechanisms of onset of diet promoted CRC as it is mediated by a decrease in expression and secretion of ISPP1.
New developments in basic and applied adiponectin research toward reduction of dementia risk and realization of healthy longevity
Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
Date (from‐to) : 2019/04 -2022/03
Author : Kadowaki Takashi
Given that the action of adiponectin and its receptors (AdipoRs) is shown to become diminished with the onset of obesity leading to the onset of metabolic syndrome, type 2 diabetes, and atherosclerosis. This research project has aimed to achieve new breakthroughs in AdipoR research through elucidation of novel mechanisms of action of AdipoR signal transduction and their biological implications in glucose/lipid metabolism as well as cell stress reduction. This promoted fundamental drug discovery research leading to the reduction of diabetic complications, such as dementia and atherosclerosis.
New developments in basic and applied adiponectin research toward reduction of dementia risk and realization of healthy longevityJapan Society for the Promotion of Science:Grants-in-Aid for Scientific...See More
New developments in basic and applied adiponectin research toward reduction of dementia risk and realization of healthy longevity
Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
Date (from‐to) : 2019/04 -2022/03
Author : Kadowaki Takashi
Given that the action of adiponectin and its receptors (AdipoRs) is shown to become diminished with the onset of obesity leading to the onset of metabolic syndrome, type 2 diabetes, and atherosclerosis. This research project has aimed to achieve new breakthroughs in AdipoR research through elucidation of novel mechanisms of action of AdipoR signal transduction and their biological implications in glucose/lipid metabolism as well as cell stress reduction. This promoted fundamental drug discovery research leading to the reduction of diabetic complications, such as dementia and atherosclerosis.
Elucidation of the cause of diabetes in the Japanese population using whole genome information and development of diagnostic and therapeutic methods using iPS cells
Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
Date (from‐to) : 2018/04 -2021/03
Author : Yamauchi Toshimasa
AFunctional analysis of variants of the type 2 diabetes susceptibility gene region was performed. It was shown that two different variants of the same gene region could regulate the expression of different genes in different tissues (Nature 2020). As a result of performing chromatin immunoprecipitation sequence and evaluating which transcription factor binding site the variant accumulates, FOXA2 and the like were found (Nat Genet 2020). We have shown that the GP2 variant can be a molecular mechanism for both type 2 diabetes and pancreatic cancer (Nat Commun 2020). When an Asian characteristic variant was expressed in pancreatic β-cells, GLP-1R altered insulin secretion (Nat Genet 2019) and PAX4 showed abnormal expression of endoplasmic reticulum calcium chaperone (HGV 2021). Genome editing was added to iPS cells, and functional analysis of variants in diabetic target cells was also performed (unpublished).
Elucidation of the cause of diabetes in the Japanese population using whole genome information and development of diagnostic and therapeutic methods using iPS cellsJapan Society for the Promotion of S...See More
Elucidation of the cause of diabetes in the Japanese population using whole genome information and development of diagnostic and therapeutic methods using iPS cells
Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
Date (from‐to) : 2018/04 -2021/03
Author : Yamauchi Toshimasa
AFunctional analysis of variants of the type 2 diabetes susceptibility gene region was performed. It was shown that two different variants of the same gene region could regulate the expression of different genes in different tissues (Nature 2020). As a result of performing chromatin immunoprecipitation sequence and evaluating which transcription factor binding site the variant accumulates, FOXA2 and the like were found (Nat Genet 2020). We have shown that the GP2 variant can be a molecular mechanism for both type 2 diabetes and pancreatic cancer (Nat Commun 2020). When an Asian characteristic variant was expressed in pancreatic β-cells, GLP-1R altered insulin secretion (Nat Genet 2019) and PAX4 showed abnormal expression of endoplasmic reticulum calcium chaperone (HGV 2021). Genome editing was added to iPS cells, and functional analysis of variants in diabetic target cells was also performed (unpublished).
Comprehensive and expansive research of the universal metabolic regulation mechanisms for healthspan
Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
This research theme is intended to establish the methodology for the elucidation of universal metabolic pathways involved in promoting healthspan as well as for the realization of healthspan. To this end, to date, our laboratory has not only successfully established the science and methodology of calorie restriction appropriate and conducive to lifespan prolongation in higher forms of life and identified universal signaling pathways involved in regulating healthspan, but has also successfully screened preclinical candidate compounds for antidiabetic and healthspan-promoting drugs in its pursuit of the science and methodology for the realization of healthspan in humans, which involves, as a basis, relevant metabolism-regulating pathways.
Comprehensive and expansive research of the universal metabolic regulation mechanisms for healthspanJapan Society for the Promotion of Science:Grants-in-Aid for Scientific ResearchDate (from‐to) : 20...See More
Comprehensive and expansive research of the universal metabolic regulation mechanisms for healthspan
Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
This research theme is intended to establish the methodology for the elucidation of universal metabolic pathways involved in promoting healthspan as well as for the realization of healthspan. To this end, to date, our laboratory has not only successfully established the science and methodology of calorie restriction appropriate and conducive to lifespan prolongation in higher forms of life and identified universal signaling pathways involved in regulating healthspan, but has also successfully screened preclinical candidate compounds for antidiabetic and healthspan-promoting drugs in its pursuit of the science and methodology for the realization of healthspan in humans, which involves, as a basis, relevant metabolism-regulating pathways.
The investigation and analysis for developing next-generation functional foods against lifestyle-related diseases
Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
The aim of this research was to generate scientific evidence for vegetables, fruits and their processed products that may serve as a basis for developing next-generation functional foods directed toward promoting adiponectin/AdipoR action, thereby establishing novel preventive measures against lifestyle-related diseases. In this research, vegetable ingredients/functional substances with lifestyle-related disease-counteractive properties were identified in experiments using cultured cells. Again, all identified vegetable ingredients/functional substances were examined for their glucose-lowering properties in animal models of lifestyle-related diseases (in preparation). Furthermore, these vegetable ingredients/functional substances were examined for their acute and chronic toxicity profile to explore their potential for product development.
The investigation and analysis for developing next-generation functional foods against lifestyle-related diseasesJapan Society for the Promotion of Science:Grants-in-Aid for Scientific ResearchDate (f...See More
The investigation and analysis for developing next-generation functional foods against lifestyle-related diseases
Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
The aim of this research was to generate scientific evidence for vegetables, fruits and their processed products that may serve as a basis for developing next-generation functional foods directed toward promoting adiponectin/AdipoR action, thereby establishing novel preventive measures against lifestyle-related diseases. In this research, vegetable ingredients/functional substances with lifestyle-related disease-counteractive properties were identified in experiments using cultured cells. Again, all identified vegetable ingredients/functional substances were examined for their glucose-lowering properties in animal models of lifestyle-related diseases (in preparation). Furthermore, these vegetable ingredients/functional substances were examined for their acute and chronic toxicity profile to explore their potential for product development.
Pathophysiological roles of adipokines in the regulation of gut microbiota in life-style related diseases
Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
We tried to clarify the mechanisms by which high-fat diet results in life-style related diseases, especially we studied interactions between immune cells and metabolism cells as well as gut microbiota and enteral metabolites. We analyzed the effects of high-fat diet, reduction in adiponectin/AdipoR actions, AdipoR activation, and transplantation of gut microbiota from AdipoR deficient mice into germfree mice. Our results raised the possibility that reduction in AdipoR actions could result in increased inflammation and oxidative stress and so on, leading to dysregulation of gut microbiota and enteral metabolites, which could worsen fatty liver, NASH, atherosclerosis, conversely AdipoR activation could ameliorate them.
Pathophysiological roles of adipokines in the regulation of gut microbiota in life-style related diseasesJapan Society for the Promotion of Science:Grants-in-Aid for Scientific ResearchDate (from‐to) ...See More
Pathophysiological roles of adipokines in the regulation of gut microbiota in life-style related diseases
Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
We tried to clarify the mechanisms by which high-fat diet results in life-style related diseases, especially we studied interactions between immune cells and metabolism cells as well as gut microbiota and enteral metabolites. We analyzed the effects of high-fat diet, reduction in adiponectin/AdipoR actions, AdipoR activation, and transplantation of gut microbiota from AdipoR deficient mice into germfree mice. Our results raised the possibility that reduction in AdipoR actions could result in increased inflammation and oxidative stress and so on, leading to dysregulation of gut microbiota and enteral metabolites, which could worsen fatty liver, NASH, atherosclerosis, conversely AdipoR activation could ameliorate them.
Building and establishing platform technologies for Structure Based Drug Design targeting AdipoR
Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
We have so far clarified that adiponectin, an adipocyte-secreted physiologically active substance, is decreased with the onset of obesity and that lifestyle-related diseases are primarily accounted for by the systemically decreased action of adiponectin/adiponectin receptors (AdipoRs). We were the first in the world to succeed in identifying small-molecule compounds that serve as seed compounds for candidate AdipoR-activating drugs. In the process, we have also reported the crystal structures of AdipoRs, which allowed the seed compounds to be structurally developed, examined for their anti-diabetic properties at the cellular and organism levels, and optimized as candidate compounds for clinical development, with their activity, specificity and safety highly enhanced over those of existing small-molecule AdipoR-activating compounds. It is hoped that these milestones will lead to the development of novel anti-diabetic drugs.
Building and establishing platform technologies for Structure Based Drug Design targeting AdipoRJapan Society for the Promotion of Science:Grants-in-Aid for Scientific ResearchDate (from‐to) : 2014/0...See More
Building and establishing platform technologies for Structure Based Drug Design targeting AdipoR
Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
We have so far clarified that adiponectin, an adipocyte-secreted physiologically active substance, is decreased with the onset of obesity and that lifestyle-related diseases are primarily accounted for by the systemically decreased action of adiponectin/adiponectin receptors (AdipoRs). We were the first in the world to succeed in identifying small-molecule compounds that serve as seed compounds for candidate AdipoR-activating drugs. In the process, we have also reported the crystal structures of AdipoRs, which allowed the seed compounds to be structurally developed, examined for their anti-diabetic properties at the cellular and organism levels, and optimized as candidate compounds for clinical development, with their activity, specificity and safety highly enhanced over those of existing small-molecule AdipoR-activating compounds. It is hoped that these milestones will lead to the development of novel anti-diabetic drugs.
Regulation of lipid accumulation by new diabetes susceptible genes and the role of the epigenome
Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
In this study, we found that expression of CDKAL1 - one of susceptible genes for type 2 diabetes and obesity identified in genome-wide association studies - is regulated during adipocyte differentiation, hypertrophy and adiposity. Functionally, CDKAL1 works as a factor that suppresses adipocyte differentiation and lipid accumulation. Mechanistically, we found that CDKAL1 stimulates the Wnt/β-catenin pathway, which suppresses adipocyte differentiation. We also mapped a promoter region responsible for the suppression of adiponectin gene expression in adipocyte hypertrophy. A transcription factor named Heb1 binds and regulates transcription. Expression level of Heb1 itlsef is regulated by various metabolic stress signals in adipocytes.
Regulation of lipid accumulation by new diabetes susceptible genes and the role of the epigenomeJapan Society for the Promotion of Science:Grants-in-Aid for Scientific ResearchDate (from‐to) : 2011/0...See More
Regulation of lipid accumulation by new diabetes susceptible genes and the role of the epigenome
Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
In this study, we found that expression of CDKAL1 - one of susceptible genes for type 2 diabetes and obesity identified in genome-wide association studies - is regulated during adipocyte differentiation, hypertrophy and adiposity. Functionally, CDKAL1 works as a factor that suppresses adipocyte differentiation and lipid accumulation. Mechanistically, we found that CDKAL1 stimulates the Wnt/β-catenin pathway, which suppresses adipocyte differentiation. We also mapped a promoter region responsible for the suppression of adiponectin gene expression in adipocyte hypertrophy. A transcription factor named Heb1 binds and regulates transcription. Expression level of Heb1 itlsef is regulated by various metabolic stress signals in adipocytes.
Pathophysiological Roles of AdipoR1/AdipoR2 in the Prevention of Atherosclerosis
Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
Date (from‐to) : 2012/04 -2014/03
Author : IWABU Miki
The adipocyte-derived hormone adiponectin has been proposed to play the central roles as antidiabetic and antiatherogenic adipokine. However, whether adiponectin receptors AdipoR1 and AdipoR2 have the protective roles against atherosclerosis in vivo are still undetermined.Therefore, in this study we investigated the in vivo roles of AdipoR1 and AdipoR2 on atherosclerosis using conventional or tissue-specific AdipoR1 and/or AdipoR2 knockout or transgenic mice as well as transplantation of bone marrow from AdipoR knockout mice.
This study provides the direct evidence that AdipoR2 in endothelial cells and AdipoR1 in macrophages play protective roles against atherosclerosis in vivo.
Pathophysiological Roles of AdipoR1/AdipoR2 in the Prevention of AtherosclerosisJapan Society for the Promotion of Science:Grants-in-Aid for Scientific ResearchDate (from‐to) : 2012/04 -2014/03 Autho...See More
Pathophysiological Roles of AdipoR1/AdipoR2 in the Prevention of Atherosclerosis
Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
Date (from‐to) : 2012/04 -2014/03
Author : IWABU Miki
The adipocyte-derived hormone adiponectin has been proposed to play the central roles as antidiabetic and antiatherogenic adipokine. However, whether adiponectin receptors AdipoR1 and AdipoR2 have the protective roles against atherosclerosis in vivo are still undetermined.Therefore, in this study we investigated the in vivo roles of AdipoR1 and AdipoR2 on atherosclerosis using conventional or tissue-specific AdipoR1 and/or AdipoR2 knockout or transgenic mice as well as transplantation of bone marrow from AdipoR knockout mice.
This study provides the direct evidence that AdipoR2 in endothelial cells and AdipoR1 in macrophages play protective roles against atherosclerosis in vivo.
Insulin signaling in endothelial cells (insulin receptor substrate) and atherosclerosis
Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
We previously demonstrated that both insulin receptor substrate (Irs) 1 knockout (KO) and Irs2 KO mice showed insulin resistance, hypertension, and hypercholesterolemia to a similar degree. Irs2 KO mice, however, exhibited much greater neointimal formation in response to cuff-injury than Irs1 KO mice. Irs2 is mainly expressed in endothelial cells. To more precisely determine the roles of Irs2 in vascular endothelial cells, we generated endothelial cell-specific Irs2 knockdown (ETIrs2KO) mice. Endothelial-dependent vascular relaxation in response to insulin was significantly impaired in ETIrs2KO mice. ETIrs2KO mice also showed mild hypertension and impaired insulin-stimulated phosphorylation of eNOS. ETIrs2KO mice were fertile and normal metabolic parameter. Interestingly, insulin resistance and glucose intolerance were observed in ETIrs2KO mice. In hyperinsulinemic-euglycemic clamp, glucose infusion rate (GIR) and rate of glucose disappearance (Rd) were significantly lower in ETIrs2KO mice than wild-type mice, whereas endogenous glucose production (EGP) did not differ between ETIrs2KO and wild-type mice. These data indicate that ETIrs2KO mice showed insulin resistance in skeletal muscle. Consistent with this, ETIrs2KO mice showed impaired insulin-stimulated phosphorylation of Akt in skeletal muscle after hyperinsulinemic-euglycemic clamp. ETIrs2KO mice also showed decreased blood flow in skeletal muscle after hyperinsulinemic-euglycemic clamp. These data suggest that the skeletal muscle insulin resistance observed in the ETIrs2KO mice may, at least in part, be caused by the decrease in skeletal muscle blood flow. To clarify the role of Irs2 of endothelial cells in atherosclerosis, we would like to examine neointimal formation response to cuff-injury in ETIrs2KO mice in the future.
Insulin signaling in endothelial cells (insulin receptor substrate) and atherosclerosisJapan Society for the Promotion of Science:Grants-in-Aid for Scientific ResearchDate (from‐to) : 2005 -2006 Auth...See More
Insulin signaling in endothelial cells (insulin receptor substrate) and atherosclerosis
Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
We previously demonstrated that both insulin receptor substrate (Irs) 1 knockout (KO) and Irs2 KO mice showed insulin resistance, hypertension, and hypercholesterolemia to a similar degree. Irs2 KO mice, however, exhibited much greater neointimal formation in response to cuff-injury than Irs1 KO mice. Irs2 is mainly expressed in endothelial cells. To more precisely determine the roles of Irs2 in vascular endothelial cells, we generated endothelial cell-specific Irs2 knockdown (ETIrs2KO) mice. Endothelial-dependent vascular relaxation in response to insulin was significantly impaired in ETIrs2KO mice. ETIrs2KO mice also showed mild hypertension and impaired insulin-stimulated phosphorylation of eNOS. ETIrs2KO mice were fertile and normal metabolic parameter. Interestingly, insulin resistance and glucose intolerance were observed in ETIrs2KO mice. In hyperinsulinemic-euglycemic clamp, glucose infusion rate (GIR) and rate of glucose disappearance (Rd) were significantly lower in ETIrs2KO mice than wild-type mice, whereas endogenous glucose production (EGP) did not differ between ETIrs2KO and wild-type mice. These data indicate that ETIrs2KO mice showed insulin resistance in skeletal muscle. Consistent with this, ETIrs2KO mice showed impaired insulin-stimulated phosphorylation of Akt in skeletal muscle after hyperinsulinemic-euglycemic clamp. ETIrs2KO mice also showed decreased blood flow in skeletal muscle after hyperinsulinemic-euglycemic clamp. These data suggest that the skeletal muscle insulin resistance observed in the ETIrs2KO mice may, at least in part, be caused by the decrease in skeletal muscle blood flow. To clarify the role of Irs2 of endothelial cells in atherosclerosis, we would like to examine neointimal formation response to cuff-injury in ETIrs2KO mice in the future.