The Center for Biotechnology and Genomic Medicine's (CBGM) research efforts focus on two main areas: 1) discovery and validation of biomarkers for disease prediction and diagnosis, 2) pharmacomics and drug discovery for personalized medicine. CBGM is home of four internationally renowned programs in diabetes research: The Environmental Determinants of Diabetes in the Young (TEDDY), the Prospective Assessment in Newborns of Diabetes Autoimmunity (PANDA), the Diabetic Complications Consortium (DCC) and the Mouse Metabolic Phenotype Consortium (MMPC). Additional research programs include autoimmune diseases, transplantation, and cancer. These research programs are supported by an annual extramural funding of approximately $12 million.

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  • A novel subnetwork based analysis reveals shared pathways in T-cell mediated autoimmunity

    Pabla, Simarjot Singh; Center for Biotechnology and Genomic Medicine (2016-03)
    Thymocyte auto-reactivity is an underlying theme of several autoimmune disorders. The precise role of auto-reactive T cells in the initiation and subsequent progression of autoimmune disorders has been studied extensively. However, these disease specific studies ignore pathways that may be in common to several T cell mediated autoimmune pathologies. This can be attributed in part to the shortcomings of traditional gene list based gene expression studies. Here we report a novel method to identify unifying gene expression changes in several autoimmune diseases. In order to uncover pathologically important pathways common to T-cell mediated autoimmune disorders, we used human gene expression data from Multiple Sclerosis, Rheumatoid Arthritis, Juvenile Idiopathic Arthritis and Sjögren’s syndrome. Unlike traditional gene expression analysis, we used jointly active connected subnetwork enrichment to identify subnetworks for each disorder, followed by topological network alignment, which led to identification of shared pathways. We report four pathways shared in these disorders, which include DNA damage response, gonadotropin, innate and adaptive immunity pathways. Importantly, our method did not reveal any common pathways in unrelated diseases. In order to experimentally validate our findings, RNA sequencing of mRNA isolated from salivary glands excised from a murine model of Sjögren’s syndrome was performed. High similarities were observed between Human T-cell mediated autoimmune disorders and Sjögren’s murine model. Collectively, these studies have identified a shared landscape of pathologically significant pathways, including DNA damage response, gonadotropin, innate and adaptive immunity in autoimmune disorders and provide a new methodology to identify common alterations in diseases with similar underlying etiologies.
  • The Autoimmune Regulator (Aire) Confers Immunosuppressive Properties to Dendritic Cells

    Eisenman, Daniel; Center for Biotechnology and Genomic Medicine (2007-05)
    The Autoimmune regulator (Aire) is a transcription factor that controls expression of self antigens by thymic epithelium and it plays a critical role in the deletion of autoreactive thymocytes and prevention of autoimmunity. Recent studies have reported Aire expression in dendritic cells (DC) located in spleen and lymph nodes, suggesting a role for Aire in extra-thymic tolerance induction. Molecular and functional studies conducted in this dissertation revealed that Aire induction in bone marrow derived DC results in expression of immunosuppressive cytokines and decreased expression of co-stimulatory molecules. Similar results were also obtained from lenti-virus-mediated Aire overexpression in the DC2.4 dendritic cell line. It was further shown that DC from Aire'7' mice exhibited greater antigen presenting function both in vitro and in vivo. These DC were more potent stimulators of T cell proliferation leading to increased IL-2 and IFNy production. These studies suggest that Aire7' DC may play a role in exacerbating the autoimmunity seen in Aire7' mice. DC over-expressing Aire were shown to suppress activation and proliferation of naive T cells and promote activation-induced cell death of activated T cells. Furthermore, we demonstrate that Aire also controls transcription of tissue-specific antigens in DC. These results, together, suggest that Aire plays an important role in the tolerogenic function of DC.
  • Large Scale Gene Expression Analysis Reveals Insight into Pathways Related to Type 1 Diabetes and Associated Complications

    Carey, Colleen M.; Center for Biotechnology and Genomic Medicine (2013-08)
    Type 1 Diabetes (T1D) is a chronic inflammatory disease resulting from complex interactions between susceptibility genes, the environment, and the immune system, ultimately leading to the destruction o f pancreatic islet cells and insulin deficiency. Previous studies have examined the series o f molecular, cellular, and protein changes occurring within subsets of individuals and how these are associated with particular disease states. Genome wide association studies have revealed a large number o f genetic susceptibility intervals including those implicated in disease pathogenesis, the identification o f various markers for risk assessment, the classification o f disease or complications, and finally markers for monitoring therapies for disease. However, none of these studies to date is without seriously limitations. First, although microarray based gene expression profiling is a powerful tool in discovery; results must be validated by alternate techniques. Second, due to the inherent heterogeneity of the human population large sample sizes in each group must be used in order to handle the expected large expression variations among individual subject. Third, for accurate normalization of Real-Time PCR expression data appropriate reference genes must be selected. We proposed a large scale gene expression validation study to address the limitations of previous studies. Validation studies were performed using high throughput Real-Time RT-PCR on peripheral blood mononuclear cells (PBMCs) o f 928 individuals with T1D and 922 individuals as antibody negative (AbN) controls, recruited through the Prospective Assessment in Newborns of Diabetes Autoimmunity (PANDA) study. This dissertation work validated the gene expression changes among 28 genes shown to have differential expression in T1D patients as compared to controls. These genes were selected based on their function, role in inflammatory or the immune response, and any previously documented reference to a role in T1D. Our aims were to 1) identify gene expression changes which may be occurring specifically in diabetic complications, and 2) identify gene expression changes which may result in an increased state o f oxidative stress in the diabetic state. For validation studies, we divided the 28 genes into two subsets based on related function to ask whether any gene expression signatures could be associated with diabetes, diabetic complications, or oxidative stress in the diabetic state. Our studies revealed genes that are involved in inflammation, immune regulation, and antigen processing and presentation are significantly altered in the PBMCs o f T1D patients. Eight genes (S100A8, S100A9, MNDA, SELL, TGFB1, PSMB3, CD74, and IL12A) were shown to have higher expression, with three genes (GNLY, PSMA4, and SMAD7) having lower expression, in T1D when compared to controls. The data also suggested that inflammatory mediators secreted mainly by myeloid cells are implicated in T1D and its complications (Odds ratios OR = 1.3-2.6, adjusted P value= 0.005- 1.08 x 10 8), and particularly in those patients with nephropathy (OR=4.8-7.9, adjusted P value < 0.005). Validation studies also revealed nine genes (LAT2, MAPK1, APOBEC3B, SOD2, NDUFB3, STK40, PRKD2, ITGB2, and COX7B) with higher expression in T1D. These genes are involved in general pathways of inflammation and immune response; however SOD2, NDUFB3, and COX7B (OR=l.l-1.27, adjusted P value= 0.007-0.47) are functionally involved in the mechanisms o f the mitochondria and may play a role in the increased state of oxidative stress seen in T1D. In these studies we have validated and confirmed the gene expression differences between T1D and control subjects initially suggested by microarray. Our experimental design has addressed each of the limitations posed by earlier studies in the largest scale study to date on gene expression profiles in human T1D. We have demonstrated that gene expression is significantly different between autoantibody negative (AbN) controls and T1D patients without any complications. Genes implicated in immune function (S100A8, S100A9, MNDA, IL12A), immune regulation and promotion (TGFB1, SELL), antigen processing and presentation (CD74, PSMB3), and mitochondrial function (SOD2, NDUFB3, COX7B) have higher expression in T1D and support the notion that chronic inflammation and cellular oxidative stress contribute to the development of T1D and associated complications. The understanding gained from our results implies a translational potential for the use o f gene expression profiles in the classification o f at risk individuals for both T1D and complication. Further, our understanding into the role that the immune system plays in cellular oxidative stress leading to the diabetic state may serve to provide prevention therapies however there remains much to be learned before this is attainable.
  • Lack of an association of miR-938 SNP in IDDM10 with human type 1 diabetes

    Mi, Xiaofan; He, Hongzhi; Deng, Yangxin; Levin, Abert M; She, Jin-Xiong; Mi, Qing-Sheng; Zhou, Li; Center for Biotechnology and Genomic Medicine (2011-10-20)
    MicroRNAs (miRNAs) are a newly discovered type of small non-protein coding RNA that function in the inhibition of effective mRNA translation, and may serve as susceptibility genes for various disease developments. The SNP rs12416605, located in human type 1 diabetes IDDM10 locus, changes the seeding sequence (UGU[G/A]CCC) of miRNA miR-938 and potentially alters miR-938 targets, including IL-16 and IL-17A. In an attempt to test whether miR-938 may be a susceptibility gene for IDDM10, we assessed the possible association of the miR-938 SNP with T1D in an American Caucasian cohort of 622 patients and 723 healthy controls by TaqMan assay. Our current data do not support the association between the SNP in miR-938 and type 1 diabetes.
  • Reduced Serum Vitamin Dâ Binding Protein Levels Are Associated With Type 1 Diabetes

    Blanton, Dustin; Han, Zhao; Bierschenk, Lindsey; Linga-Reddy, M.V. Prasad; Wang, Hongjie; Clare-Salzler, Michael; Haller, Michael; Schatz, Desmond; Myhr, Courtney; She, Jin-Xiong; et al. (2011-10-16)
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  • Influence of common variants in FTO and near INSIG2 and MC4R on growth curves for adiposity in Africanâ and Europeanâ American youth

    Liu, Gaifen; Zhu, Haidong; Dong, Yanbin; Podolsky, Robert H.; Treiber, Frank A.; Snieder, Harold; Center for Biotechnology and Genomic Medicine (2011-06-5)
    Electronic supplementary material: The online version of this article (doi:10.1007/s10654-011-9583-4) contains supplementary material, which is available to authorized users.
  • The Role of Endoplasmic Reticulum Stress in Autoimmune-Mediated Beta-Cell Destruction in Type 1 Diabetes

    Zhong, Jixin; Rao, Xiaoquan; Xu, Jun-Fa; Yang, Ping; Wang, Cong-Yi; Center for Biotechnology and Genomic Medicine (2012-02-14)
    Unlike type 2 diabetes which is caused by the loss of insulin sensitivity, type 1 diabetes (T1D) is manifested by the absolute deficiency of insulin secretion due to the loss of β mass by autoimmune response against β-cell self-antigens. Although significant advancement has been made in understanding the pathoetiology for type 1 diabetes, the exact mechanisms underlying autoimmune-mediated β-cell destruction, however, are yet to be fully addressed. Accumulated evidence demonstrates that endoplasmic reticulum (ER) stress plays an essential role in autoimmune-mediated β-cell destruction. There is also evidence supporting that ER stress regulates the functionality of immune cells relevant to autoimmune progression during T1D development. In this paper, we intend to address the role of ER stress in autoimmune-mediated β-cell destruction during the course of type 1 diabetes. The potential implication of ER stress in modulating autoimmune response will be also discussed. We will further dissect the possible pathways implicated in the induction of ER stress and summarize the potential mechanisms underlying ER stress for mediation of β-cell destruction. A better understanding of the role for ER stress in T1D pathoetiology would have great potential aimed at developing effective therapeutic approaches for the prevention/intervention of this devastating disorder.
  • Country-specific birth weight and length in type 1 diabetes high-risk HLA genotypes in combination with prenatal characteristics

    Sterner, Y; Torn, C; Lee, H-S; Larsson, H; Winkler, C; McLeod, W; Lynch, K; Simell, O; Ziegler, A; Schatz, Desmond; et al. (2011-04-28)
    Objective
  • Critical role of Bcl11b in suppressor function of T regulatory cells and prevention of inflammatory bowel disease

    VanValkenburgh, Jeffrey; Albu, Diana I.; Bapanpally, Chandra; Casanova, Sarah; Califano, Danielle; Jones, David M.; Ignatowicz, Leszek; Kawamoto, Shimpei; Fagarasan, Sidonia; Jenkins, Nancy A.; et al. (2011-09-26)
    Dysregulated CD4+ T cell responses and alterations in T regulatory cells (Treg cells) play a critical role in autoimmune diseases, including inflammatory bowel disease (IBD). The current study demonstrates that removal of Bcl11b at the double-positive stage of T cell development or only in Treg cells causes IBD because of proinflammatory cytokine-producing CD4+ T cells infiltrating the colon. Provision of WT Treg cells prevented IBD, demonstrating that alterations in Treg cells are responsible for the disease. Furthermore, Bcl11b-deficient Treg cells had reduced suppressor activity with altered gene expression profiles, including reduced expression of the genes encoding Foxp3 and IL-10, and up-regulation of genes encoding proinflammatory cytokines. Additionally, the absence of Bcl11b altered the induction of Foxp3 expression and reduced the generation of induced Treg cells (iTreg cells) after Tgf-b treatment of conventional CD4+ T cells. Bcl11b bound to Foxp3 and IL-10 promoters, as well as to critical conserved noncoding sequences within the Foxp3 and IL-10 loci, and mutating the Bcl11b binding site in the Foxp3 promoter reduced expression of a luciferase reporter gene. These experiments demonstrate that Bcl11b is indispensable for Treg suppressor function and for maintenance of optimal Foxp3 and IL-10 gene expression, as well as for the induction of Foxp3 expression in conventional CD4+ T cells in response to Tgf-b and generation of iTreg cells.
  • Chemokine (C-C Motif) Ligand 2 (CCL2) in Sera of Patients with Type 1 Diabetes and Diabetic Complications

    Guan, Ruili; Purohit, Sharad; Wang, Hongjie; Bode, Bruce; Reed, John Chip; Steed, R. Dennis; Anderson, Stephen W.; Steed, Leigh; Hopkins, Diane; Xia, Chun; et al. (2011-04-12)
    Background: Chemokine (C-C motif) ligand 2 (CCL2), commonly known as monocyte chemoattractant protein-1 (MCP-1), has been implicated in the pathogenesis of many diseases characterized by monocytic infiltration. However, limited data have been reported on MCP-1 in type 1 diabetes (T1D) and the findings are inconclusive and inconsistent.
  • Intratumoral Convergence of the TCR Repertoires of Effector and Foxp3+ CD4+ T cells

    Kuczma, Michal; Kopij, Magdalena; Pawlikowska, Iwona; Wang, Cong-Yi; Rempala, Grzegorz A.; Kraj, Piotr; Center for Biotechnology and Genomic Medicine; Department of Biostatistics and Epidemiology; GHSU Cancer Center (2010-10-26)
    The presence of Foxp3+ regulatory CD4+ T cells in tumor lesions is considered one of the major causes of ineffective immune response in cancer. It is not clear whether intratumoral Treg cells represent Treg cells pre-existing in healthy mice, or arise from tumor-specific effector CD4+ T cells and thus representing adaptive Treg cells. The generation of Treg population in tumors could be further complicated by recent evidence showing that both in humans and mice the peripheral population of Treg cells is heterogenous and consists of subsets which may differentially respond to tumor-derived antigens. We have studied Treg cells in cancer in experimental mice that express naturally selected, polyclonal repertoire of CD4+ T cells and which preserve the heterogeneity of the Treg population. The majority of Treg cells present in healthy mice maintained a stable suppressor phenotype, expressed high level of Foxp3 and an exclusive set of TCRs not used by naive CD4+ T cells. A small Treg subset, utilized TCRs shared with effector T cells and expressed a lower level of Foxp3. We show that response to tumor-derived antigens induced efficient clonal recruitment and expansion of antigen-specific effector and Treg cells. However, the population of Treg cells in tumors was dominated by cells expressing TCRs shared with effector CD4+ T cells. In contrast, Treg cells expressing an exclusive set of TCRs, that dominate in healthy mice, accounted for only a small fraction of all Treg cells in tumor lesions. Our results suggest that the Treg repertoire in tumors is generated by conversion of effector CD4+ T cells or expansion of a minor subset of Treg cells. In conclusion, successful cancer immunotherapy may depend on the ability to block upregulation of Foxp3 in effector CD4+ T cells and/or selectively inhibiting the expansion of a minor Treg subset.
  • A statistical framework for integrating two microarray data sets in differential expression analysis.

    Lai, Yinglei; Eckenrode, Sarah E; She, Jin-Xiong; Center for Biotechnology and Genomic Medicine (2009-02-11)
    BACKGROUND: Different microarray data sets can be collected for studying the same or similar diseases. We expect to achieve a more efficient analysis of differential expression if an efficient statistical method can be developed for integrating different microarray data sets. Although many statistical methods have been proposed for data integration, the genome-wide concordance of different data sets has not been well considered in the analysis. RESULTS: Before considering data integration, it is necessary to evaluate the genome-wide concordance so that misleading results can be avoided. Based on the test results, different subsequent actions are suggested. The evaluation of genome-wide concordance and the data integration can be achieved based on the normal distribution based mixture models. CONCLUSION: The results from our simulation study suggest that misleading results can be generated if the genome-wide concordance issue is not appropriately considered. Our method provides a rigorous parametric solution. The results also show that our method is robust to certain model misspecification and is practically useful for the integrative analysis of differential expression.
  • Molecular cloning and characterization of the mouse Acdp gene family.

    Wang, Cong-Yi; Yang, Ping; Shi, Jing-Da; Purohit, Sharad; Guo, Dehuang; An, Haiqian; Gu, Jian-Guo; Ling, Jennifer X; Dong, Zheng; She, Jin-Xiong; et al. (2004-05-11)
    BACKGROUND: We have recently cloned and characterized a novel gene family named ancient conserved domain protein (ACDP) in humans. To facilitate the functional study of this novel gene family, we have cloned and characterized Acdp, the mouse homologue of the human ACDP gene family. RESULTS: The four Acdp genes (Acdp1, Acdp2, Acdp3 and Acdp4) contain 3,631 bp, 3,244 bp, 2,684 bp and 2,743 bp of cDNA sequences, and encode deduced proteins of 951, 874, 713 and 771 amino acids, respectively. The mouse Acdp genes showed very strong homologies (>90%) in both nucleotide and amino acid sequences to their human counterparts. In addition, both nucleotide and amino acid sequences within the Ancient Conserved Domain (ACD) are highly conserved in many different taxonomic species. Particularly, Acdp proteins showed very strong AA homologies to the bacteria CorC protein (35% AA identity with 55% homology), which is involved in magnesium and cobalt efflux. The Acdp genes are widely expressed in all tissues tested except for Acdp1, which is only highly expressed in the brain with low levels of expression in kidney and testis. Immunostaining of Acdp1 in hippocampus neurons revealed a predominant localization on the plasma membrane. CONCLUSION: The Acdp genes are evolutionarily conserved in diverse species and ubiquitously expressed throughout development and adult tissues suggesting that Acdp may be an essential gene. Acdp showed strong homology to bacteria CorC protein and predominantly localized on the plasma membrane. These results suggest that Acdp is probably a family of proteins involved in ion transport in mammalian cells
  • Physical interaction and functional coupling between ACDP4 and the intracellular ion chaperone COX11, an implication of the role of ACDP4 in essential metal ion transport and homeostasis.

    Guo, Dehuang; Ling, Jennifer X; Wang, Mong-Heng; She, Jin-Xiong; Gu, Jianguo; Wang, Cong-Yi; Center for Biotechnology and Genomic Medicine; Department of Physiology (2008-01-16)
    Divalent metal ions such as copper, manganese, and cobalt are essential for cell development, differentiation, function and survival. These essential metal ions are delivered into intracellular domains as cofactors for enzymes involved in neuropeptide and neurotransmitter synthesis, superoxide metabolism, and other biological functions in a target specific fashion. Altering the homeostasis of these essential metal ions is known to connect to a number of human diseases including Alzheimer disease, amyotrophic lateral sclerosis, and pain. It remains unclear how these essential metal ions are delivered to intracellular targets in mammalian cells. Here we report that rat spinal cord dorsal horn neurons express ACDP4, a member of Ancient Conserved Domain Protein family. By screening a pretransformed human fetal brain cDNA library in a yeast two-hybrid system, we have identified that ACDP4 specifically interacts with COX11, an intracellular metal ion chaperone. Ectopic expression of ACDP4 in HEK293 cells resulted in enhanced toxicity to metal ions including copper, manganese, and cobalt. The metal ion toxicity became more pronounced when ACDP4 and COX11 were co-expressed ectopically in HEK293 cells, suggesting a functional coupling between them. Our results indicate a role of ACDP4 in metal ion homeostasis and toxicity. This is the first report revealing a functional aspect of this ancient conserved domain protein family. We propose that ACDP is a family of transporter protein or chaperone proteins for delivering essential metal ions in different mammalian tissues. The expression of ACDP4 on spinal cord dorsal horn neurons may have implications in sensory neuron functions under physiological and pathological conditions.
  • Alterations of renal phenotype and gene expression profiles due to protein overload in NOD-related mouse strains.

    Wilson, Karen H S; McIndoe, Richard A; Eckenrode, Sarah E; Morel, Laurence; Agarwal, Anupam; Croker, Byron P; She, Jin-Xiong; Center for Biotechnology and Genomic Medicine (2006-01-19)
    BACKGROUND: Despite multiple causes, Chronic Kidney Disease is commonly associated with proteinuria. A previous study on Non Obese Diabetic mice (NOD), which spontaneously develop type 1 diabetes, described histological and gene expression changes incurred by diabetes in the kidney. Because proteinuria is coincident to diabetes, the effects of proteinuria are difficult to distinguish from those of other factors such as hyperglycemia. Proteinuria can nevertheless be induced in mice by peritoneal injection of Bovine Serum Albumin (BSA). To gain more information on the specific effects of proteinuria, this study addresses renal changes in diabetes resistant NOD-related mouse strains (NON and NOD.B10) that were made to develop proteinuria by BSA overload. METHODS: Proteinuria was induced by protein overload on NON and NOD.B10 mouse strains and histology and microarray technology were used to follow the kidney response. The effects of proteinuria were assessed and subsequently compared to changes that were observed in a prior study on NOD diabetic nephropathy. RESULTS: Overload treatment significantly modified the renal phenotype and out of 5760 clones screened, 21 and 7 kidney transcripts were respectively altered in the NON and NOD.B10. Upregulated transcripts encoded signal transduction genes, as well as markers for inflammation (Calmodulin kinase beta). Down-regulated transcripts included FKBP52 which was also down-regulated in diabetic NOD kidney. Comparison of transcripts altered by proteinuria to those altered by diabetes identified mannosidase 2 alpha 1 as being more specifically induced by proteinuria. CONCLUSION: By simulating a component of diabetes, and looking at the global response on mice resistant to the disease, by virtue of a small genetic difference, we were able to identify key factors in disease progression. This suggests the power of this approach in unraveling multifactorial disease processes.
  • Genetically dependent ERBB3 expression modulates antigen presenting cell function and type 1 diabetes risk.

    Wang, Hongjie; Jin, Yulan; Reddy, M V Prasad Linga; Podolsky, Robert H.; Liu, Siyang; Yang, Ping; Bode, Bruce; Reed, John Chip; Steed, R. Dennis; Anderson, Stephen W.; et al. (2010-07-29)
    Type 1 diabetes (T1D) is an autoimmune disease resulting from the complex interaction between multiple susceptibility genes, environmental factors and the immune system. Over 40 T1D susceptibility regions have been suggested by recent genome-wide association studies; however, the specific genes and their role in the disease remain elusive. The objective of this study is to identify the susceptibility gene(s) in the 12q13 region and investigate the functional link to the disease pathogenesis. A total of 19 SNPs in the 12q13 region were analyzed by the TaqMan assay for 1,434 T1D patients and 1,865 controls. Thirteen of the SNPs are associated with T1D (best p = 4x10(-11)), thus providing confirmatory evidence for at least one susceptibility gene in this region. To identify candidate genes, expression of six genes in the region was analyzed by real-time RT-PCR for PBMCs from 192 T1D patients and 192 controls. SNP genotypes in the 12q13 region are the main factors that determine ERBB3 mRNA levels in PBMCs. The protective genotypes for T1D are associated with higher ERBB3 mRNA level (p<10(-10)). Furthermore, ERBB3 protein is expressed on the surface of CD11c(+) cells (dendritic cells and monocytes) in peripheral blood after stimulation with LPS, polyI:C or CpG. Subjects with protective genotypes have significantly higher percentages of ERBB3(+) monocytes and dendritic cells (p = 1.1x10(-9)); and the percentages of ERBB3(+) cells positively correlate with the ability of APC to stimulate T cell proliferation (R(2) = 0.90, p<0.0001). Our results indicate that ERBB3 plays a critical role in determining APC function and potentially T1D pathogenesis.
  • Hepatic gene expression profiling reveals key pathways involved in leptin-mediated weight loss in ob/ob mice.

    Sharma, Ashok; Bartell, Shoshana M; Baile, Clifton A; Chen, Bo; Podolsky, Robert H.; McIndoe, Richard A; She, Jin-Xiong; Center for Biotechnology and Genomic Medicine; Department of Medicine; Department of Pathology (2010-09-02)
    BACKGROUND: Leptin, a cytokine-like protein, plays an important role in the regulation of body weight through inhibition of food intake and stimulation of energy expenditure. Leptin circulates in blood and acts on the brain, which sends downstream signals to regulate body weight. Leptin therapy has been successful in treating leptin deficient obese patients. However, high levels of leptin have been observed in more common forms of obesity indicating a state of leptin resistance which limits the application of leptin in the treatment of obesity. If the central effect of leptin could be by-passed and genes which respond to leptin treatment could be regulated directly, new therapeutic targets for the treatment of obesity may be possible. The purpose of this study was to identify genes and subsequent pathways correlated with leptin-mediated weight loss. METHODOLOGY/PRINCIPAL FINDINGS: WE UTILIZED MICROARRAY TECHNOLOGY TO COMPARE HEPATIC GENE EXPRESSION CHANGES AFTER TWO TYPES OF LEPTIN ADMINISTRATION: one involving a direct stimulatory effect when administered peripherally (subcutaneous: SQ) and another that is indirect, involving a hypothalamic relay that suppresses food intake when leptin is administered centrally (intracerebroventricular: ICV). We identified 214 genes that correlate with leptin mediated weight loss. Several biological processes such as mitochondrial metabolic pathways, lipid metabolic and catabolic processes, lipid biosynthetic processes, carboxylic acid metabolic processes, iron ion binding and glutathione S-transferases were downregulated after leptin administration. In contrast, genes involved in the immune system inflammatory response and lysosomal activity were found to be upregulated. Among the cellular compartments mitochondrion (32 genes), endoplasmic reticulum (22 genes) and vacuole (8 genes) were significantly over represented. CONCLUSIONS/SIGNIFICANCE: In this study we have identified key molecular pathways and downstream genes which respond to leptin treatment and are involved in leptin-mediated weight loss. Many of these genes have previously been shown to be associated with obesity; however, we have also identified a number of other novel target genes. Further investigation will be required to assess the possible use of these genes and their associated protein products as therapeutic targets for the treatment of obesity.
  • Loss of Jak2 selectively suppresses DC-mediated innate immune response and protects mice from lethal dose of LPS-induced septic shock.

    Zhong, Jixin; Yang, Ping; Muta, Kenjiro; Dong, Robert; Marrero, Mario; Gong, Feili; Wang, Cong-Yi; Center for Biotechnology and Genomic Medicine; Vascular Biology Center (2010-03-16)
    Given the importance of Jak2 in cell signaling, a critical role for Jak2 in immune cells especially dendritic cells (DCs) has long been proposed. The exact function for Jak2 in DCs, however, remained poorly understood as Jak2 deficiency leads to embryonic lethality. Here we established Jak2 deficiency in adult Cre(+/+)Jak2(fl/fl) mice by tamoxifen induction. Loss of Jak2 significantly impaired DC development as manifested by reduced BMDC yield, smaller spleen size and reduced percentage of DCs in total splenocytes. Jak2 was also crucial for the capacity of DCs to mediate innate immune response. Jak2(-/-) DCs were less potent in response to inflammatory stimuli and showed reduced capacity to secrete proinflammatory cytokines such as TNFalpha and IL-12. As a result, Jak2(-/-) mice were defective for the early clearance of Listeria after infection. However, their potency to mediate adaptive immune response was not affected. Unlike DCs, Jak2(-/-) macrophages showed similar capacity secretion of proinflammatory cytokines, suggesting that Jak2 selectively modulates innate immune response in a DC-dependent manner. Consistent with these results, Jak2(-/-) mice were remarkably resistant to lethal dose of LPS-induced septic shock, a deadly sepsis characterized by the excessive innate immune response, and adoptive transfer of normal DCs restored their susceptibility to LPS-induced septic shock. Mechanistic studies revealed that Jak2/SATA5 signaling is pivotal for DC development and maturation, while the capacity for DCs secretion of proinflammatory cytokines is regulated by both Jak2/STAT5 and Jak2/STAT6 signaling.
  • Genetic and Molecular Basis of QTL of Diabetes in Mouse: Genes and Polymorphisms.

    Gao, Peng; Jiao, Yan; Xiong, Qing; Wang, Cong-Yi; Gerling, Ivan; Gu, Weikuan; Center for Biotechnology and Genomic Medicine (2009-05-27)
    A systematic study has been conducted of all available reports in PubMed and OMIM (Online Mendelian Inheritance in Man) to examine the genetic and molecular basis of quantitative genetic loci (QTL) of diabetes with the main focus on genes and polymorphisms. The major question is, What can the QTL tell us? Specifically, we want to know whether those genome regions differ from other regions in terms of genes relevant to diabetes. Which genes are within those QTL regions, and, among them, which genes have already been linked to diabetes? whether more polymorphisms have been associated with diabetes in the QTL regions than in the non-QTL regions.Our search revealed a total of 9038 genes from 26 type 1 diabetes QTL, which cover 667,096,006 bp of the mouse genomic sequence. On one hand, a large number of candidate genes are in each of these QTL; on the other hand, we found that some obvious candidate genes of QTL have not yet been investigated. Thus, the comprehensive search of candidate genes for known QTL may provide unexpected benefit for identifying QTL genes for diabetes.
  • Differential gene expression in the salivary gland during development and onset of xerostomia in Sj??gren's syndrome-like disease of the C57BL/6.NOD-Aec1Aec2 mouse.

    Nguyen, Cuong Q; Sharma, Ashok; Lee, Byung Ha; She, Jin-Xiong; McIndoe, Richard A; Peck, Ammon B; Center for Biotechnology and Genomic Medicine (2009-05-28)
    INTRODUCTION: Recently, we reported the development of the C57BL/6.NOD-Aec1Aec2 mouse that carries two genetic intervals derived from the non-obese diabetic (NOD) mouse capable of conferring Sj??gren's syndrome (SjS)-like disease in SjS-non-susceptible C57BL/6 mice. In an attempt to define the molecular bases underlying the onset of stomatitis sicca (xerostomia) in this C57BL/6.NOD-Aec1Aec2 mouse model, we have carried out a study using genomic microarray technology. METHODS: By means of oligonucleotide microarrays, gene expression profiles of salivary glands at 4, 8, 12, 16, and 20 weeks of age were generated for C57BL/6.NOD-Aec1Aec2 male mice. Using Linear Models for Microarray Analysis and B-statistics software, 480 genes were identified as being differentially expressed (P < 0.01 and Q < 0.0001) during the development of SjS-like disease in the salivary glands. RESULTS: The 480 genes could be arranged into four clusters, with each cluster defining a unique pattern of temporal expression, while the individual genes within each cluster could be grouped according to related biological functions. By means of pair-wise analysis, temporal changes in transcript expressions provided profiles indicating that many additional genes are differentially expressed at specific time points during the development of disease. Multiple genes reportedly showing an association with autoimmunity and/or SjS, in either humans or mouse models, were found to exhibit differential expressions, both quantitatively and temporally. Selecting various families of genes associated with specific functions (for example, antibody production, complement, and chemokines), we noted that only a limited number of family members showed differential expressions and these correlated with specific phases of disease. CONCLUSIONS: Taking advantage of known functions of these genes, investigators can construct interactive gene pathways, leading to modeling of possible underlying events inducing salivary gland dysfunction. Thus, these different approaches to analyzing microarray data permit the identification of multiple sets of genes of interest whose expressions and expression profiles may correlate with molecular mechanisms, signaling pathways, and/or immunological processes involved in the development and onset of SjS.

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