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Satoshi Takaki - One of the best experts on this subject based on the ideXlab platform.

  • Lnk/SH2B3 Regulates Adipose Inflammation and Glucose Tolerance through Group 1 ILCs.
    Cell reports, 2018
    Co-Authors: Taizo Mori, Nao Suzuki-yamazaki, Satoshi Takaki
    Abstract:

    Summary Lnk/SH2B3 is an adaptor protein that negatively regulates cytokine signaling in lymphohematopoiesis. A missense variant within the LNK/SH2B3 gene has been reported to be a risk variant for several autoimmune diseases, including diabetes. We found that glucose tolerance and insulin responses were impaired in Lnk−/− mice. Moreover, immune cells such as group 1 innate lymphoid cells (G1-ILCs), CD8+ T cells, and M1 macrophages accumulated in adipose tissue. When Lnk−/− mice were crossed with Il15−/− mice or depleted of G1-ILCs but not CD8+ T cells, glucose intolerance and adipose inflammation were ameliorated. Lnk−/− G1-ILCs showed activated phenotypes as well as enhanced reactivity for IL-15, and administration of a JAK inhibitor improved glucose tolerance. Accordingly, a high-fat diet greatly worsened glucose intolerance in Lnk−/− mice. Thus, Lnk/SH2B3 controls homeostasis in adipose tissue and reduces the risk of onset of diabetes by regulating the expansion and activation of IL-15-dependent adipose G1-ILCs.

  • lnk SH2B3 regulates adipose inflammation and glucose tolerance through group 1 ilcs
    Cell Reports, 2018
    Co-Authors: Taizo Mori, Nao Suzukiyamazaki, Satoshi Takaki
    Abstract:

    Summary Lnk/SH2B3 is an adaptor protein that negatively regulates cytokine signaling in lymphohematopoiesis. A missense variant within the LNK/SH2B3 gene has been reported to be a risk variant for several autoimmune diseases, including diabetes. We found that glucose tolerance and insulin responses were impaired in Lnk−/− mice. Moreover, immune cells such as group 1 innate lymphoid cells (G1-ILCs), CD8+ T cells, and M1 macrophages accumulated in adipose tissue. When Lnk−/− mice were crossed with Il15−/− mice or depleted of G1-ILCs but not CD8+ T cells, glucose intolerance and adipose inflammation were ameliorated. Lnk−/− G1-ILCs showed activated phenotypes as well as enhanced reactivity for IL-15, and administration of a JAK inhibitor improved glucose tolerance. Accordingly, a high-fat diet greatly worsened glucose intolerance in Lnk−/− mice. Thus, Lnk/SH2B3 controls homeostasis in adipose tissue and reduces the risk of onset of diabetes by regulating the expansion and activation of IL-15-dependent adipose G1-ILCs.

  • lnk SH2B3 controls the production and function of dendritic cells and regulates the induction of ifn γ producing t cells
    Journal of Immunology, 2014
    Co-Authors: Taizo Mori, Yukiko Iwasaki, Yoichi Seki, Masanori Iseki, Hiroko Katayama, Kazuhiko Yamamoto, Kiyoshi Takatsu, Satoshi Takaki
    Abstract:

    Dendritic cells (DCs) are proficient APCs that play crucial roles in the immune responses to various Ags and pathogens and polarize Th cell immune responses. Lnk/SH2B adaptor protein 3 (SH2B3) is an intracellular adaptor protein that regulates B lymphopoiesis, megakaryopoiesis, and expansion of hematopoietic stem cells by constraining cytokine signals. Recent genome-wide association studies have revealed a link between polymorphism in this adaptor protein and autoimmune diseases, including type 1 diabetes and celiac disease. We found that Lnk/SH2B3 was also expressed in DCs and investigated its role in the production and function of DC lineage cells. In Lnk −/− mice, DC numbers were increased in the spleen and lymph nodes, and growth responses of bone marrow–derived DCs to GM-CSF were augmented. Mature DCs from Lnk −/− mice were hypersensitive and showed enhanced responses to IL-15 and GM-CSF. Compared to normal DCs, Lnk −/− DCs had enhanced abilities to support the differentiation of IFN-γ–producing Th1 cells from naive CD4 + T cells. This was due to their elevated expression of IL-12Rβ1 and increased production of IFN-γ. Lnk −/− DCs supported the appearance of IFN-γ–producing T cells even under conditions in which normal DCs supported induction of regulatory T cells. These results indicated that Lnk/SH2B3 plays a regulatory role in the expansion of DCs and might influence inflammatory immune responses in peripheral lymphoid tissues.

  • Lnk/SH2B3 controls the production and function of dendritic cells and regulates the induction of IFN-γ-producing T cells.
    Journal of immunology (Baltimore Md. : 1950), 2014
    Co-Authors: Taizo Mori, Yukiko Iwasaki, Yoichi Seki, Masanori Iseki, Hiroko Katayama, Kazuhiko Yamamoto, Kiyoshi Takatsu, Satoshi Takaki
    Abstract:

    Dendritic cells (DCs) are proficient APCs that play crucial roles in the immune responses to various Ags and pathogens and polarize Th cell immune responses. Lnk/SH2B adaptor protein 3 (SH2B3) is an intracellular adaptor protein that regulates B lymphopoiesis, megakaryopoiesis, and expansion of hematopoietic stem cells by constraining cytokine signals. Recent genome-wide association studies have revealed a link between polymorphism in this adaptor protein and autoimmune diseases, including type 1 diabetes and celiac disease. We found that Lnk/SH2B3 was also expressed in DCs and investigated its role in the production and function of DC lineage cells. In Lnk −/− mice, DC numbers were increased in the spleen and lymph nodes, and growth responses of bone marrow–derived DCs to GM-CSF were augmented. Mature DCs from Lnk −/− mice were hypersensitive and showed enhanced responses to IL-15 and GM-CSF. Compared to normal DCs, Lnk −/− DCs had enhanced abilities to support the differentiation of IFN-γ–producing Th1 cells from naive CD4 + T cells. This was due to their elevated expression of IL-12Rβ1 and increased production of IFN-γ. Lnk −/− DCs supported the appearance of IFN-γ–producing T cells even under conditions in which normal DCs supported induction of regulatory T cells. These results indicated that Lnk/SH2B3 plays a regulatory role in the expansion of DCs and might influence inflammatory immune responses in peripheral lymphoid tissues.

  • homeostasis of hematopoietic stem cells regulated by the myeloproliferative disease associated gene product lnk SH2B3 via bcl xl
    Experimental Hematology, 2012
    Co-Authors: Nao Suzuki, Satoshi Yamazaki, Hideo Ema, Tomoyuki Yamaguchi, Hiromitsu Nakauchi, Satoshi Takaki
    Abstract:

    Hematopoietic stem cells (HSCs) are maintained at a very low frequency in adult bone marrow under steady-state conditions. However, it is not fully understood how homeostasis of bone marrow HSCs is maintained. We attempted to identify a key molecule involved in the regulation of HSC numbers, a factor that, in the absence of Lnk, leads to HSC expansion. Here, we demonstrate that upon stimulation with thrombopoietin, expression of Bcl-xL, an antiapoptotic protein, was highly enhanced in Lnk-deficient HSCs compared to normal HSCs. As a result, Lnk-deficient HSCs underwent reduced apoptosis following exposure to lethal radiation. Downregulation of Bcl-xL expression in Lnk-deficient HSCs by short-hairpin RNA resulted in a great reduction of their capacity for reconstitution. These findings suggest that Lnk/SH2B3 constrains the expression of Bcl-xL and that the loss of Lnk/SH2B3 function enhances survival of HSCs by inhibiting apoptosis. Furthermore, our observations indicate that HSCs in patients with an Lnk/SH2B3 mutation might become resistant to apoptosis due to thrombopoietin-mediated enhanced expression of Bcl-xL. Consequently, reduced apoptosis could facilitate accumulation of HSCs with oncogenic mutations leading to development of myeloproliferative disorders.

Nan Wang - One of the best experts on this subject based on the ideXlab platform.

  • Sex-specific association of SH2B3 and SMARCA4 polymorphisms with coronary artery disease susceptibility.
    Oncotarget, 2017
    Co-Authors: Yanbin Song, Qingwen Wang, Zhao Zhao, Nan Wang, Tianbo Jin, Chao Chen
    Abstract:

    // Yuqiang Ji 1, 2, 3, * , Yanbin Song 1, 2, 4, * , Qingwen Wang 5 , Pengcheng Xu 5 , Zhao Zhao 3 , Xia Li 3 , Nan Wang 3 , Tianbo Jin 1, 2 and Chao Chen 1, 2 1 Key Laboratory of Resource Biology and Biotechnology in Western China, Northwest University, Ministry of Education, Xi’an, Shaanxi 710069, China 2 School of Life Sciences, Northwest University, Xi’an, Shaanxi 710069, China 3 Department of Cardiovascular Medicine, First Hospital of Xi’an, Xi’an 710002, China 4 Department of Cardiovascular Medicine, Affiliated Hospital Yan’an University, Yan’an 716000, China 5 Department of Hand Surgery, Hebei Province Cangzhou Hospital of integrated Traditional and Western Medicine, Cangzhou, Hebei 061001, China * These authors have contributed equally to this work Correspondence to: Tianbo Jin, email: jintianbo@gmail.com Chao Chen, email: cchen898@nwu.edu.cn Keywords: coronary artery disease, SH2B3 , SMARCA4 , single nucleotide polymorphism, gene Received: February 06, 2017     Accepted: June 03, 2017     Published: July 31, 2017 ABSTRACT To determine whether sex differences affect the association between genetic polymorphisms and coronary artery disease (CAD) in the Chinese Han population, we conducted a study comparing the frequency of SH2B3 and SMARCA4 variants in 456 CAD patients (291 men, 165 women) and 685 age-matched controls (385 men, 300 women). Ten single nucleotide polymorphisms (SNPs) in SH2B3 and SMARCA4 were genotyped using MassARRAY technology. Allelic and genotypic models and haplotype frequencies were compared between groups. Logistic regression was used to estimate the CAD risk associated with the genotypes. We found that the “A” alleles in both rs11879293 and rs12232780 of SMARCA4 were associated with CAD risk in men ( p = 0.036 and p = 0.001, respectively). The genetic model showed that SH2B3 was associated with CAD susceptibility in both women and men, while SMARCA4 was associated with reduced odds of CAD in men. SH2B3 haplotypes were associated with decreased CAD risk in women ( p = 0.007) and increased CAD risk in men ( p = 0.047).By providing evidence for the sex-related association between SH2B3 and SMARCA4 gene variants and CAD susceptibility in the Chinese Han population, this study may help define useful diagnostic and preventive markers for these patients.

  • lnk SH2B3 loss of function promotes atherosclerosis and thrombosis
    Circulation Research, 2016
    Co-Authors: Wei Wang, Y Wang, Yang Tang, Joanna Balcerek, Wei Tong, Ross L. Levine, Carrie L. Welch, Alan R. Tall, Liana Tascau, Nan Wang
    Abstract:

    Rationale:Human genome-wide association studies have revealed novel genetic loci that are associated with coronary heart disease. One such locus resides in LNK/SH2B3, which in mice is expressed in hematopoietic cells and suppresses thrombopoietin signaling via its receptor myeloproliferative leukemia virus oncogene. However, the mechanisms underlying the association of LNK single-nucleotide polymorphisms with coronary heart disease are poorly understood. Objective:To understand the functional effects of LNK single-nucleotide polymorphisms and explore the mechanisms whereby LNK loss of function impacts atherosclerosis and thrombosis. Methods and Results:Using human cord blood, we show that the common TT risk genotype (R262W) of LNK is associated with expansion of hematopoietic stem cells and enhanced megakaryopoiesis, demonstrating reduced LNK function and increased myeloproliferative leukemia virus oncogene signaling. In mice, hematopoietic Lnk deficiency leads to accelerated arterial thrombosis and ather...

  • LNK/SH2B3 Loss of Function Promotes Atherosclerosis and Thrombosis
    Circulation research, 2016
    Co-Authors: Wei Wang, Y Wang, Yang Tang, Joanna Balcerek, Wei Tong, Ross L. Levine, Carrie L. Welch, Alan R. Tall, Liana Tascau, Nan Wang
    Abstract:

    Rationale:Human genome-wide association studies have revealed novel genetic loci that are associated with coronary heart disease. One such locus resides in LNK/SH2B3, which in mice is expressed in hematopoietic cells and suppresses thrombopoietin signaling via its receptor myeloproliferative leukemia virus oncogene. However, the mechanisms underlying the association of LNK single-nucleotide polymorphisms with coronary heart disease are poorly understood. Objective:To understand the functional effects of LNK single-nucleotide polymorphisms and explore the mechanisms whereby LNK loss of function impacts atherosclerosis and thrombosis. Methods and Results:Using human cord blood, we show that the common TT risk genotype (R262W) of LNK is associated with expansion of hematopoietic stem cells and enhanced megakaryopoiesis, demonstrating reduced LNK function and increased myeloproliferative leukemia virus oncogene signaling. In mice, hematopoietic Lnk deficiency leads to accelerated arterial thrombosis and ather...

  • SH2B3/LNK Loss of Function Promotes Atherosclerosis and Thrombosis
    Blood, 2015
    Co-Authors: Wei Wang, Y Wang, Yang Tang, Joanna Balcerek, Wei Tong, Ross L. Levine, Carrie L. Welch, Alan R. Tall, Nan Wang
    Abstract:

    Human genome-wide association studies (GWAS) have revealed many novel genetic loci that are associated with coronary heart disease (CHD) but do not involve traditional risk factors. However, the relevant genes and mechanisms are largely unknown. One such locus resides in SH2B3/LNK , which is expressed in hematopoietic cells and suppresses thrombopoietin (TPO) signaling via its receptor (MPL). The common risk single nucleotide polymorphism (SNP) of SH2B3 / LNK is associated with CHD, increased platelet and myeloid cell counts in peripheral blood and JAK2V617F positive myeloproliferative neoplasms. Analysis of human cord blood revealed that samples with TT risk SNP (R262W) in SH2B3 / LNK was associated with expansion of hematopoietic stem cells (HSCs), increased MPL signaling in HSCs, increased megakaryopoiesis, and a paradoxical increased expression of LNK mRNA, indicating reduced LNK function but induction of LNK transcription downstream of increased MPL signaling. Since humans are hypercholesterolemic relative to mice, to assess the role of reduced LNK function in athero-thrombosis, we transplanted WT or Lnk-/- bone marrow (BM) cells into irradiated WT or low-density lipoprotein receptor knock-out (Ldlr-/-) recipient mice and fed the recipients with chow and western type diet (WTD), respectively. Although Lnk-/- BM recipients showed similarly increased platelet counts on both diets, we found that platelet activation and aggregation, formation of platelet/leukocyte aggregates, atherosclerosis and arterial thrombosis were markedly increased by the combination of hyperlipidemia and hematopoietic LNK deficiency. These diet-genotype interactions mirrored an increase in mean platelet volume, protease-activated receptor-4 (PAR4) agonist-induced P-selectin exposure on platelets and platelet protein kinase C (PKC) activity, suggesting increased platelet granule secretion. We also observed an increased number of bone marrow myeloid progenitor cells expressing elevated levels of the common-beta subunit (CBS) of the interleukin-3/granulocyte-macrophage colony-stimulating factor (IL-3/GM-CSF) receptor, which promotes leukocytosis and the formation of platelet/leukocyte aggregates in the bloodstream. The increased P-selectin exposure, platelet aggregation and PKC activity were largely reversed by high-density lipoprotein (HDL) or cyclodextrin, reagents that remove cholesterol from platelets. Consistently, cholesterol loading of platelets from the chow-fed mice led to increased P-selectin exposure and PKC activity upon PAR4 agonist stimulation but the increase was more pronounced in Lnk-/- platelets, indicating a cholesterol-genotype interaction. LNK deficiency also resulted in defective MPL-mediated TPO internalization in platelets, leading to increased plasma TPO levels in mice on both diets. Elevated TPO levels and enhanced MPL signaling likely acted together to increase the pool of HSCs and megakaryopoiesis, leading to marked thrombocytosis. These studies suggest that SH2B3/LNK loss of function variants lead to HSC expansion, overproduction of platelets, and in the setting of hypercholesterolemia, markedly increased myeloid cells, platelet activation and formation of platelet/leukocyte aggregates, leading to accelerated atherosclerosis and arterial thrombosis. Our studies point to the importance of treating dyslipidemia in the setting of platelet and myeloid cell overproduction, as observed in subjects with SH2B3/LNK risk alleles. Disclosures Levine: Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Foundation Medicine: Consultancy. Tall: Amgen: Consultancy; Arisaph: Consultancy; CSL: Consultancy.

  • SH2B3 lnk loss of function promotes atherosclerosis and thrombosis
    Blood, 2015
    Co-Authors: Wei Wang, Y Wang, Yang Tang, Joanna Balcerek, Wei Tong, Ross L. Levine, Carrie L. Welch, Alan R. Tall, Nan Wang
    Abstract:

    Human genome-wide association studies (GWAS) have revealed many novel genetic loci that are associated with coronary heart disease (CHD) but do not involve traditional risk factors. However, the relevant genes and mechanisms are largely unknown. One such locus resides in SH2B3/LNK , which is expressed in hematopoietic cells and suppresses thrombopoietin (TPO) signaling via its receptor (MPL). The common risk single nucleotide polymorphism (SNP) of SH2B3 / LNK is associated with CHD, increased platelet and myeloid cell counts in peripheral blood and JAK2V617F positive myeloproliferative neoplasms. Analysis of human cord blood revealed that samples with TT risk SNP (R262W) in SH2B3 / LNK was associated with expansion of hematopoietic stem cells (HSCs), increased MPL signaling in HSCs, increased megakaryopoiesis, and a paradoxical increased expression of LNK mRNA, indicating reduced LNK function but induction of LNK transcription downstream of increased MPL signaling. Since humans are hypercholesterolemic relative to mice, to assess the role of reduced LNK function in athero-thrombosis, we transplanted WT or Lnk-/- bone marrow (BM) cells into irradiated WT or low-density lipoprotein receptor knock-out (Ldlr-/-) recipient mice and fed the recipients with chow and western type diet (WTD), respectively. Although Lnk-/- BM recipients showed similarly increased platelet counts on both diets, we found that platelet activation and aggregation, formation of platelet/leukocyte aggregates, atherosclerosis and arterial thrombosis were markedly increased by the combination of hyperlipidemia and hematopoietic LNK deficiency. These diet-genotype interactions mirrored an increase in mean platelet volume, protease-activated receptor-4 (PAR4) agonist-induced P-selectin exposure on platelets and platelet protein kinase C (PKC) activity, suggesting increased platelet granule secretion. We also observed an increased number of bone marrow myeloid progenitor cells expressing elevated levels of the common-beta subunit (CBS) of the interleukin-3/granulocyte-macrophage colony-stimulating factor (IL-3/GM-CSF) receptor, which promotes leukocytosis and the formation of platelet/leukocyte aggregates in the bloodstream. The increased P-selectin exposure, platelet aggregation and PKC activity were largely reversed by high-density lipoprotein (HDL) or cyclodextrin, reagents that remove cholesterol from platelets. Consistently, cholesterol loading of platelets from the chow-fed mice led to increased P-selectin exposure and PKC activity upon PAR4 agonist stimulation but the increase was more pronounced in Lnk-/- platelets, indicating a cholesterol-genotype interaction. LNK deficiency also resulted in defective MPL-mediated TPO internalization in platelets, leading to increased plasma TPO levels in mice on both diets. Elevated TPO levels and enhanced MPL signaling likely acted together to increase the pool of HSCs and megakaryopoiesis, leading to marked thrombocytosis. These studies suggest that SH2B3/LNK loss of function variants lead to HSC expansion, overproduction of platelets, and in the setting of hypercholesterolemia, markedly increased myeloid cells, platelet activation and formation of platelet/leukocyte aggregates, leading to accelerated atherosclerosis and arterial thrombosis. Our studies point to the importance of treating dyslipidemia in the setting of platelet and myeloid cell overproduction, as observed in subjects with SH2B3/LNK risk alleles. Disclosures Levine: Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Foundation Medicine: Consultancy. Tall: Amgen: Consultancy; Arisaph: Consultancy; CSL: Consultancy.

David L. Mattson - One of the best experts on this subject based on the ideXlab platform.

  • The function of SH2B3 (LNK) in the kidney
    American journal of physiology. Renal physiology, 2016
    Co-Authors: Gregory Blass, David L. Mattson, Alexander Staruschenko
    Abstract:

    Recent evidence indicates the adaptor protein SH2B3 has a major role in the progression of renal diseases. SH2B3 is highly expressed by hematopoietic cells and regulates cytokine signaling, inducing cell-specific effects. Additionally, its expression in other cell types suggests that SH2B3 may have a more extensive role within the kidney. Ex vivo studies have determined targets of SH2B3 cell-specific signaling, while in vivo studies have observed the SH2B3 overall affects in the progression of renal diseases. This mini-review covers the function of SH2B3-expressing cell types that contribute to renal pathologies and their regulation by SH2B3.

  • mutation of SH2B3 lnk a gwas candidate for hypertension attenuates dahl ss hypertension via inflammatory modulation
    Hypertension, 2015
    Co-Authors: Nathan P. Rudemiller, Hayley Lund, Jessica R. C. Priestley, Bradley T. Endres, Jeremy W. Prokop, Howard J. Jacob, Aron M. Geurts, Eric P. Cohen, David L. Mattson
    Abstract:

    Human genome wide association studies (GWAS) have linked SH2B3 (LNK) to hypertension and renal disease, though little experimental investigation has been done to verify a role for SH2B3 in these pathologies. SH2B3, a member of the SH2B adaptor protein family, is an intracellular adaptor protein that functions as a negative regulator in many signaling pathways, including inflammatory signaling processes. To explore a mechanistic link between SH2B3 and hypertension, we targeted the SH2B3 gene for mutation on the Dahl salt-sensitive (SS) rat genetic background with zinc-finger nucleases (ZFN). The resulting mutation was a 6 base-pair, in-frame deletion within a highly-conserved region of the Src Homology 2 (SH2) domain of SH2B3. This mutation significantly attenuated Dahl salt-sensitive (SS) hypertension and renal disease. Also, infiltration of leukocytes into the kidneys, a key mediator of Dahl SS pathology, was significantly blunted in the SH2B3em1Mcwi mutant rats. To determine if this was due to differences in immune signaling, bone marrow transplant studies were performed in which Dahl SS and SH2B3em1Mcwi mutants underwent total body irradiation and were then transplanted with Dahl SS or SH2B3em1Mcwi mutant bone marrow. Rats that received SH2B3em1Mcwi mutant bone marrow had a significant reduction in mean arterial pressure and kidney injury when placed on a high salt diet (4% NaCl). These data further support a role for the immune system as a modulator of disease severity in the pathogenesis of hypertension and provide insight into inflammatory mechanisms at play in human hypertension and renal disease.

  • Mutation of SH2B3 (LNK), a Genome-Wide Association Study Candidate for Hypertension, Attenuates Dahl Salt-Sensitive Hypertension via Inflammatory ModulationNovelty and Significance
    Hypertension (Dallas Tex. : 1979), 2015
    Co-Authors: Nathan P. Rudemiller, Hayley Lund, Jessica R. C. Priestley, Bradley T. Endres, Jeremy W. Prokop, Howard J. Jacob, Aron M. Geurts, Eric P. Cohen, David L. Mattson
    Abstract:

    Human genome-wide association studies have linked SH2B adaptor protein 3 ( SH2B3 , LNK ) to hypertension and renal disease, although little experimental investigation has been performed to verify a role for SH2B3 in these pathologies. SH2B3, a member of the SH2B adaptor protein family, is an intracellular adaptor protein that functions as a negative regulator in many signaling pathways, including inflammatory signaling processes. To explore a mechanistic link between SH2B3 and hypertension, we targeted the SH2B3 gene for mutation on the Dahl salt-sensitive (SS) rat genetic background with zinc-finger nucleases. The resulting mutation was a 6-bp, in-frame deletion within a highly conserved region of the Src homology 2 (SH2) domain of SH2B3 . This mutation significantly attenuated Dahl SS hypertension and renal disease. Also, infiltration of leukocytes into the kidneys, a key mediator of Dahl SS pathology, was significantly blunted in the SH2B3 em1Mcwi mutant rats. To determine whether this was because of differences in immune signaling, bone marrow transplant studies were performed in which Dahl SS and SH2B3 em1Mcwi mutants underwent total body irradiation and were then transplanted with Dahl SS or SH2B3 em1Mcwi mutant bone marrow. Rats that received SH2B3 em1Mcwi mutant bone marrow had a significant reduction in mean arterial pressure and kidney injury when placed on a high salt diet (4% NaCl). These data further support a role for the immune system as a modulator of disease severity in the pathogenesis of hypertension and provide insight into inflammatory mechanisms at play in human hypertension and renal disease.

  • Abstract 006: Mutation of SH2B3, a GWAS Candidate Gene for Hypertension, Attenuates Dahl SS Pathology
    Hypertension, 2014
    Co-Authors: Nathan P. Rudemiller, Hayley Lund, Aron M. Geurts, David L. Mattson
    Abstract:

    The immune system mediates hypertension in many experimental models, though the mechanisms remain unclear. In the Dahl salt-sensitive (SS) rat, infiltration of T lymphocytes and macrophages in the kidneys parallels the onset of hypertension and renal disease in response to high salt diet (4% NaCl). Immunosuppressive treatment blunts the infiltration of immune cells in the kidneys and attenuates the hypertensive pathology. SH2B3, a gene associated with human hypertension in many GWAS, encodes an intracellular adaptor protein shown to play an important role in inflammatory signaling. Mutation of SH2B3 via zinc-finger nucleases on the Dahl SS genetic background reduces immune cell infiltration in the kidneys and significantly attenuates the hypertensive pathology. Bone marrow transplant studies (n=5-6/group; below) show that Dahl SS or SH2B3 mutant rats receiving the SH2B3 mutant bone marrow (open circles, light bars) have significantly attenuated hypertension and albuminuria compared to rats receiving the Dahl SS bone marrow (closed circles, dark bars; * indicates P These studies indicate a role for the immune system in the altered phenotype in the SH2B3 mutant rat. One possible immune mechanism involved is interleukin 6 (IL-6) signaling, a proinflammatory pathway in which SH2B3 functions. After 21 days on 4% NaCl diet (n=5-6/group), SH2B3 mutants have significantly lower mRNA expression of IL-6 (expressed as fold change of Dahl SS) in the renal cortex (0.54, p

  • Mutation of SH2B3 attenuates Dahl SS hypertension via inflammatory signaling (1136.15)
    The FASEB Journal, 2014
    Co-Authors: Nathan P. Rudemiller, Hayley Lund, Jessica R. C. Priestley, Aron M. Geurts, David L. Mattson
    Abstract:

    Previous studies implicate infiltrating immune cells in the kidney in the pathogenesis of Dahl salt sensitive hypertension. SH2B3, an adaptor protein shown to participate in vascular and inflammato...

Nathan P. Rudemiller - One of the best experts on this subject based on the ideXlab platform.

  • mutation of SH2B3 lnk a gwas candidate for hypertension attenuates dahl ss hypertension via inflammatory modulation
    Hypertension, 2015
    Co-Authors: Nathan P. Rudemiller, Hayley Lund, Jessica R. C. Priestley, Bradley T. Endres, Jeremy W. Prokop, Howard J. Jacob, Aron M. Geurts, Eric P. Cohen, David L. Mattson
    Abstract:

    Human genome wide association studies (GWAS) have linked SH2B3 (LNK) to hypertension and renal disease, though little experimental investigation has been done to verify a role for SH2B3 in these pathologies. SH2B3, a member of the SH2B adaptor protein family, is an intracellular adaptor protein that functions as a negative regulator in many signaling pathways, including inflammatory signaling processes. To explore a mechanistic link between SH2B3 and hypertension, we targeted the SH2B3 gene for mutation on the Dahl salt-sensitive (SS) rat genetic background with zinc-finger nucleases (ZFN). The resulting mutation was a 6 base-pair, in-frame deletion within a highly-conserved region of the Src Homology 2 (SH2) domain of SH2B3. This mutation significantly attenuated Dahl salt-sensitive (SS) hypertension and renal disease. Also, infiltration of leukocytes into the kidneys, a key mediator of Dahl SS pathology, was significantly blunted in the SH2B3em1Mcwi mutant rats. To determine if this was due to differences in immune signaling, bone marrow transplant studies were performed in which Dahl SS and SH2B3em1Mcwi mutants underwent total body irradiation and were then transplanted with Dahl SS or SH2B3em1Mcwi mutant bone marrow. Rats that received SH2B3em1Mcwi mutant bone marrow had a significant reduction in mean arterial pressure and kidney injury when placed on a high salt diet (4% NaCl). These data further support a role for the immune system as a modulator of disease severity in the pathogenesis of hypertension and provide insight into inflammatory mechanisms at play in human hypertension and renal disease.

  • Mutation of SH2B3 (LNK), a Genome-Wide Association Study Candidate for Hypertension, Attenuates Dahl Salt-Sensitive Hypertension via Inflammatory ModulationNovelty and Significance
    Hypertension (Dallas Tex. : 1979), 2015
    Co-Authors: Nathan P. Rudemiller, Hayley Lund, Jessica R. C. Priestley, Bradley T. Endres, Jeremy W. Prokop, Howard J. Jacob, Aron M. Geurts, Eric P. Cohen, David L. Mattson
    Abstract:

    Human genome-wide association studies have linked SH2B adaptor protein 3 ( SH2B3 , LNK ) to hypertension and renal disease, although little experimental investigation has been performed to verify a role for SH2B3 in these pathologies. SH2B3, a member of the SH2B adaptor protein family, is an intracellular adaptor protein that functions as a negative regulator in many signaling pathways, including inflammatory signaling processes. To explore a mechanistic link between SH2B3 and hypertension, we targeted the SH2B3 gene for mutation on the Dahl salt-sensitive (SS) rat genetic background with zinc-finger nucleases. The resulting mutation was a 6-bp, in-frame deletion within a highly conserved region of the Src homology 2 (SH2) domain of SH2B3 . This mutation significantly attenuated Dahl SS hypertension and renal disease. Also, infiltration of leukocytes into the kidneys, a key mediator of Dahl SS pathology, was significantly blunted in the SH2B3 em1Mcwi mutant rats. To determine whether this was because of differences in immune signaling, bone marrow transplant studies were performed in which Dahl SS and SH2B3 em1Mcwi mutants underwent total body irradiation and were then transplanted with Dahl SS or SH2B3 em1Mcwi mutant bone marrow. Rats that received SH2B3 em1Mcwi mutant bone marrow had a significant reduction in mean arterial pressure and kidney injury when placed on a high salt diet (4% NaCl). These data further support a role for the immune system as a modulator of disease severity in the pathogenesis of hypertension and provide insight into inflammatory mechanisms at play in human hypertension and renal disease.

  • SH2B3 Is a Genetic Determinant of Cardiac Inflammation and Fibrosis
    Circulation. Cardiovascular genetics, 2015
    Co-Authors: Michael J. Flister, Nathan P. Rudemiller, Aron M. Geurts, Matthew J. Hoffman, Angela Lemke, Sasha Z. Prisco, Caitlin C. O’meara, Carol Moreno, Shirng Wern Tsaih, Jozef Lazar
    Abstract:

    Background—Genome-wide association studies are powerful tools for nominating pathogenic variants, but offer little insight as to how candidate genes affect disease outcome. Such is the case for SH2...

  • Abstract 006: Mutation of SH2B3, a GWAS Candidate Gene for Hypertension, Attenuates Dahl SS Pathology
    Hypertension, 2014
    Co-Authors: Nathan P. Rudemiller, Hayley Lund, Aron M. Geurts, David L. Mattson
    Abstract:

    The immune system mediates hypertension in many experimental models, though the mechanisms remain unclear. In the Dahl salt-sensitive (SS) rat, infiltration of T lymphocytes and macrophages in the kidneys parallels the onset of hypertension and renal disease in response to high salt diet (4% NaCl). Immunosuppressive treatment blunts the infiltration of immune cells in the kidneys and attenuates the hypertensive pathology. SH2B3, a gene associated with human hypertension in many GWAS, encodes an intracellular adaptor protein shown to play an important role in inflammatory signaling. Mutation of SH2B3 via zinc-finger nucleases on the Dahl SS genetic background reduces immune cell infiltration in the kidneys and significantly attenuates the hypertensive pathology. Bone marrow transplant studies (n=5-6/group; below) show that Dahl SS or SH2B3 mutant rats receiving the SH2B3 mutant bone marrow (open circles, light bars) have significantly attenuated hypertension and albuminuria compared to rats receiving the Dahl SS bone marrow (closed circles, dark bars; * indicates P These studies indicate a role for the immune system in the altered phenotype in the SH2B3 mutant rat. One possible immune mechanism involved is interleukin 6 (IL-6) signaling, a proinflammatory pathway in which SH2B3 functions. After 21 days on 4% NaCl diet (n=5-6/group), SH2B3 mutants have significantly lower mRNA expression of IL-6 (expressed as fold change of Dahl SS) in the renal cortex (0.54, p

  • Abstract 41: SH2B3 Is a Genetic Determinant of Cardiac Inflammation and Fibrosis
    Arteriosclerosis Thrombosis and Vascular Biology, 2014
    Co-Authors: Michael J. Flister, Nathan P. Rudemiller, Aron M. Geurts, Matthew J. Hoffman, Angela Lemke, Sasha Z. Prisco, Caitlin C. O’meara, Carol Moreno, Jozef Lazar, Neeta Adhikari
    Abstract:

    Background: Genome wide association studies (GWAS) are powerful tools for nominating pathogenic variants, but offer little insight as to how candidate genes impact disease outcome. Such is the case for SH2B adaptor protein 3 (SH2B3), which is associated with coronary artery disease (CAD), atherosclerosis, and risk of myocardial infarction (MI), but its role in post-MI response is completely unknown. Methods: Using an experimental model of MI (left anterior descending artery [LAD] occlusion) in wild-type (WT) and SH2B3 knockout (KO) rats, we assessed the role of SH2B3 in post-MI fibrosis, leukocyte infiltration, angiogenesis, left ventricle (LV) contractility, and inflammatory gene expression. We also confirmed our findings in LV samples from end-stage heart failure patients with or without the MI-associated SH2B3 risk allele. Results: Compared with WT, SH2B3 KO rats had significantly increased fibrosis (2.2-fold; P2-fold; P

Aron M. Geurts - One of the best experts on this subject based on the ideXlab platform.

  • mutation of SH2B3 lnk a gwas candidate for hypertension attenuates dahl ss hypertension via inflammatory modulation
    Hypertension, 2015
    Co-Authors: Nathan P. Rudemiller, Hayley Lund, Jessica R. C. Priestley, Bradley T. Endres, Jeremy W. Prokop, Howard J. Jacob, Aron M. Geurts, Eric P. Cohen, David L. Mattson
    Abstract:

    Human genome wide association studies (GWAS) have linked SH2B3 (LNK) to hypertension and renal disease, though little experimental investigation has been done to verify a role for SH2B3 in these pathologies. SH2B3, a member of the SH2B adaptor protein family, is an intracellular adaptor protein that functions as a negative regulator in many signaling pathways, including inflammatory signaling processes. To explore a mechanistic link between SH2B3 and hypertension, we targeted the SH2B3 gene for mutation on the Dahl salt-sensitive (SS) rat genetic background with zinc-finger nucleases (ZFN). The resulting mutation was a 6 base-pair, in-frame deletion within a highly-conserved region of the Src Homology 2 (SH2) domain of SH2B3. This mutation significantly attenuated Dahl salt-sensitive (SS) hypertension and renal disease. Also, infiltration of leukocytes into the kidneys, a key mediator of Dahl SS pathology, was significantly blunted in the SH2B3em1Mcwi mutant rats. To determine if this was due to differences in immune signaling, bone marrow transplant studies were performed in which Dahl SS and SH2B3em1Mcwi mutants underwent total body irradiation and were then transplanted with Dahl SS or SH2B3em1Mcwi mutant bone marrow. Rats that received SH2B3em1Mcwi mutant bone marrow had a significant reduction in mean arterial pressure and kidney injury when placed on a high salt diet (4% NaCl). These data further support a role for the immune system as a modulator of disease severity in the pathogenesis of hypertension and provide insight into inflammatory mechanisms at play in human hypertension and renal disease.

  • Mutation of SH2B3 (LNK), a Genome-Wide Association Study Candidate for Hypertension, Attenuates Dahl Salt-Sensitive Hypertension via Inflammatory ModulationNovelty and Significance
    Hypertension (Dallas Tex. : 1979), 2015
    Co-Authors: Nathan P. Rudemiller, Hayley Lund, Jessica R. C. Priestley, Bradley T. Endres, Jeremy W. Prokop, Howard J. Jacob, Aron M. Geurts, Eric P. Cohen, David L. Mattson
    Abstract:

    Human genome-wide association studies have linked SH2B adaptor protein 3 ( SH2B3 , LNK ) to hypertension and renal disease, although little experimental investigation has been performed to verify a role for SH2B3 in these pathologies. SH2B3, a member of the SH2B adaptor protein family, is an intracellular adaptor protein that functions as a negative regulator in many signaling pathways, including inflammatory signaling processes. To explore a mechanistic link between SH2B3 and hypertension, we targeted the SH2B3 gene for mutation on the Dahl salt-sensitive (SS) rat genetic background with zinc-finger nucleases. The resulting mutation was a 6-bp, in-frame deletion within a highly conserved region of the Src homology 2 (SH2) domain of SH2B3 . This mutation significantly attenuated Dahl SS hypertension and renal disease. Also, infiltration of leukocytes into the kidneys, a key mediator of Dahl SS pathology, was significantly blunted in the SH2B3 em1Mcwi mutant rats. To determine whether this was because of differences in immune signaling, bone marrow transplant studies were performed in which Dahl SS and SH2B3 em1Mcwi mutants underwent total body irradiation and were then transplanted with Dahl SS or SH2B3 em1Mcwi mutant bone marrow. Rats that received SH2B3 em1Mcwi mutant bone marrow had a significant reduction in mean arterial pressure and kidney injury when placed on a high salt diet (4% NaCl). These data further support a role for the immune system as a modulator of disease severity in the pathogenesis of hypertension and provide insight into inflammatory mechanisms at play in human hypertension and renal disease.

  • SH2B3 Is a Genetic Determinant of Cardiac Inflammation and Fibrosis
    Circulation. Cardiovascular genetics, 2015
    Co-Authors: Michael J. Flister, Nathan P. Rudemiller, Aron M. Geurts, Matthew J. Hoffman, Angela Lemke, Sasha Z. Prisco, Caitlin C. O’meara, Carol Moreno, Shirng Wern Tsaih, Jozef Lazar
    Abstract:

    Background—Genome-wide association studies are powerful tools for nominating pathogenic variants, but offer little insight as to how candidate genes affect disease outcome. Such is the case for SH2...

  • Abstract 006: Mutation of SH2B3, a GWAS Candidate Gene for Hypertension, Attenuates Dahl SS Pathology
    Hypertension, 2014
    Co-Authors: Nathan P. Rudemiller, Hayley Lund, Aron M. Geurts, David L. Mattson
    Abstract:

    The immune system mediates hypertension in many experimental models, though the mechanisms remain unclear. In the Dahl salt-sensitive (SS) rat, infiltration of T lymphocytes and macrophages in the kidneys parallels the onset of hypertension and renal disease in response to high salt diet (4% NaCl). Immunosuppressive treatment blunts the infiltration of immune cells in the kidneys and attenuates the hypertensive pathology. SH2B3, a gene associated with human hypertension in many GWAS, encodes an intracellular adaptor protein shown to play an important role in inflammatory signaling. Mutation of SH2B3 via zinc-finger nucleases on the Dahl SS genetic background reduces immune cell infiltration in the kidneys and significantly attenuates the hypertensive pathology. Bone marrow transplant studies (n=5-6/group; below) show that Dahl SS or SH2B3 mutant rats receiving the SH2B3 mutant bone marrow (open circles, light bars) have significantly attenuated hypertension and albuminuria compared to rats receiving the Dahl SS bone marrow (closed circles, dark bars; * indicates P These studies indicate a role for the immune system in the altered phenotype in the SH2B3 mutant rat. One possible immune mechanism involved is interleukin 6 (IL-6) signaling, a proinflammatory pathway in which SH2B3 functions. After 21 days on 4% NaCl diet (n=5-6/group), SH2B3 mutants have significantly lower mRNA expression of IL-6 (expressed as fold change of Dahl SS) in the renal cortex (0.54, p

  • Abstract 41: SH2B3 Is a Genetic Determinant of Cardiac Inflammation and Fibrosis
    Arteriosclerosis Thrombosis and Vascular Biology, 2014
    Co-Authors: Michael J. Flister, Nathan P. Rudemiller, Aron M. Geurts, Matthew J. Hoffman, Angela Lemke, Sasha Z. Prisco, Caitlin C. O’meara, Carol Moreno, Jozef Lazar, Neeta Adhikari
    Abstract:

    Background: Genome wide association studies (GWAS) are powerful tools for nominating pathogenic variants, but offer little insight as to how candidate genes impact disease outcome. Such is the case for SH2B adaptor protein 3 (SH2B3), which is associated with coronary artery disease (CAD), atherosclerosis, and risk of myocardial infarction (MI), but its role in post-MI response is completely unknown. Methods: Using an experimental model of MI (left anterior descending artery [LAD] occlusion) in wild-type (WT) and SH2B3 knockout (KO) rats, we assessed the role of SH2B3 in post-MI fibrosis, leukocyte infiltration, angiogenesis, left ventricle (LV) contractility, and inflammatory gene expression. We also confirmed our findings in LV samples from end-stage heart failure patients with or without the MI-associated SH2B3 risk allele. Results: Compared with WT, SH2B3 KO rats had significantly increased fibrosis (2.2-fold; P2-fold; P