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Jin-Xiong She

Publications and source records attributed to Jin-Xiong She.

At least 19 recordsLinked to original sources
PubMed2006

Vascular endothelium summary statement VI: Research directions for the 21st century.

Effective translation of research advances from the bench to clinical and public health practice at the bedside and in the community at large represents an important step in the health research discovery enterprise. Increasingly, the gap in translating these advances into practice is being recognized. Successfully addressing this translational gap for the prevention and control of chronic diseases will require the development of novel, innovative, and, if necessary, nontraditional approaches. Participants in the 8th International Conference on Vascular Endothelium discussed a variety of novel approaches that have significant promise. Three of these approaches-vaccine development, genomics and proteomics, and tissue engineering-are highlighted in this position statement and strategies for public health practice and research are suggested.

Animals↗
PubMed2006

Early pathogenic events associated with Sjögren's syndrome (SjS)-like disease of the NOD mouse using microarray analysis.

Recently, we reported development of the C57BL/6.NOD-Aec1Aec2 mouse carrying two genetic intervals derived from the NOD mouse. These two genetic regions confer full Sjögren's syndrome (SjS)-like disease in SjS-non-susceptible C57BL/6 mice. The current study was undertaken to apply microarray technology to define the molecular basis underlying onset of SjS-disease in C57BL/6.NOD-Aec1Aec2 mice. Using oligonucleotide microarrays, gene expression profiles of submandibular glands derived from 8- to 12-week-old C57BL/6.NOD-Aec1Aec2 mice and 8-week-old C57BL/6 mice were performed for comparison. Significant differential expressions were determined using the Mann-Whitney U test. Hybridizations using submandibular cDNA probes revealed 75 differentially expressed genes at 8 weeks and 105 differentially expressed genes at 12 weeks of age in C57BL/6.NOD-Aec1Aec2 mice compared to 8-week-old C57BL/6 mice. These genes were related generally to basic cellular activities such as transcription, translation, DNA replication, and protein folding. During the predisease phase, genes upregulated encode proteins associated with the IFN-gamma signal-transduction-pathway (Jak/Stat1), TLR-3 (Irf3 and Traf6) and apoptosis (casp11 and casp3), indicative of chronic proinflammatory stimuli, especially IL-1. Between 8 and 12 weeks of age, sets of clustered genes were upregulated that are associated with adaptive immune responses, especially B cell activation, proliferation and differentiation (Baffr, Taci, Bcma, Blys, April, CD70, CD40L, Traf1, Traf3, Pax5, c-Jun, Elk1 and Nf-kB), and neural receptors (Taj/Troy). Altered gene expressions of TLR3 and TNF-superfamily-receptors and ligands during this early phase of SjS suggest a possible viral etiology in the altered glandular homeostasis with an upregulated, possibly overstimulated, B-lymphocyte activation in the early autoimmune response present in the submandibular glands. The importance of NF-kappaB as a critical signal transduction pathway is also suggested but its link is not yet clear.

Age Factors↗
PubMed2006

The autoimmune regulator (Aire) controls iNKT cell development and maturation.

The mechanism underlying the autoimmune polyglandular syndrome type-1 (APS1) has been attributed to defective T-cell negative selection resulting from reduced expression and presentation of autoantigens in thymic medullary epithelial cells (MECs). It has also been postulated that Aire is involved in development of regulatory T cells, although supporting evidence is lacking. Here we show that expression of Aire in MECs is required for development of iNKT cells, suggesting a role for iNKT cells in APS1.

Animals↗
PubMed2006

GCSF receptor regulates antigen uptake and expression of cytokines and costimulatory molecules in dendritic cells.

RNA interference (RNAi), a process that specifically silences target gene expression, is a powerful technique to modulate cellular functions. In this study, we identified two small interference RNA (siRNA) sequences that can specifically and efficiently silence the expression of the granulocyte colony-stimulating factor receptor (GCSF-R) gene and achieved stable knockdown of GCSF-R using pFIV lentivirus containing the GCSF-R siRNA. GCSF-R knockdown significantly reduces the expression of IL-lalpha, IL-lbeta, IL-6, IL-10, H-2Kb, I-Ab, CD80 and CD86, and increases PDL1 and PDL2 expression, while IL-12p35, TGFbeta, TNFalpha and CD40 expression is unaltered. Furthermore, GCSF-R knockdown significantly changes the endocytosis and micro-pinocytosis abilities as well as surface expression of antigens of DC2.4 cells.

Animals↗
PubMed2006

Assessing the utility of SELDI-TOF and model averaging for serum proteomic biomarker discovery.

The SELDI-TOF technique was used to profile serum proteins from Type 1 diabetes (T1D) patients and healthy autoantibody-negative (AbN) controls. Univariate and multivariate analyses were performed to identify putative biomarkers for T1D and to assess the reproducibility of the SELDI technique. We found 146 protein/peptide peaks (581 total peaks discovered) in human serum showing statistical differences in expression levels between T1D patients and controls, with 84% of these peaks showing technical replication. Because individual proteins did not offer great power for disease prediction, we used our model averaging approach that combines the information from multiple multivariate models to accurately classify T1D and control subjects (88.9% specificity and 90.0% sensitivity). Analyses of a test subset of the data showed less accuracy (82.8% specificity and 76.2% sensitivity), although the results are still positive. Unfortunately, no multivariate model could be replicated using the same samples. This first attempt of high throughput analyses of the human serum proteome in T1D patients suggests that model averaging is a viable method for developing biomarkers; however, the reproducibility of SELDI-TOF is currently not sufficient to be used for classification of complex diseases like T1D.

Adolescent↗
PubMed2006

Maternal understanding of infant diabetes risk: differential effects of maternal anxiety and depression.

PURPOSE: This study describes maternal understanding of infant risk associated with newborn genetic screening for type 1 diabetes. METHODS: Mothers of at-risk infants (n = 195), identified through the Prospective Assessment of Newborns for Diabetes Autoimmunity study, were notified of risk status by standardized script. Mothers participated in structured telephone interviews 1 and 3.5 months after notification that assessed understanding of infant risk and psychologic response to the news. RESULTS: Most mothers (78.5%) were accurate in their understanding of infant risk at the initial interview, with a slight decline at the follow-up interview (73%). There was a significant increase in underestimation of risk from the initial (12%) to the follow-up interview (19%) (chi2 (1) = 6.0, P = .01). Mothers with less education, those from ethnic minority backgrounds, and those who were not married tended to be less accurate. Further, mothers who experienced more anxiety and fewer depressive symptoms in response to the news were more likely to be accurate. Likewise, underestimation of risk was associated with fewer anxiety and more depressive symptoms. CONCLUSION: This study highlights the complex picture of factors promoting maternal understanding of infant diabetes risk in a sample of mothers whose newborns had been identified as at increased risk for type 1 diabetes.

Adult↗
PubMed2006

Association of the PTPN22/LYP gene with type 1 diabetes.

OBJECTIVES: The goal of this study was to verify the association between type 1 diabetes (T1D) and the protein tyrosine phosphatase, non-receptor type 22 (PTPN22) gene in non-Hispanic whites (NHWs) and Hispanics from Colorado. SUBJECTS AND METHODS: The C1858T single-nucleotide polymorphism within the PTPN22 gene was genotyped in 753 patients with T1D ascertained from the diabetes clinic at the Barbara Davis Center in Denver and 662 control population. RESULTS: Both the PTPN22 CT genotype [odds ratio (OR) = 1.96; p < 0.0001] and TT genotype (OR = 4.41; p = 0.02) were significantly associated with T1D in the NHW population. While the association was stronger in subjects with non-HLA-DR3/4 genotypes than in those with the HLA-DR3/4 genotype, regression analyses did not reveal significant interaction between PTPN22 genotypes and HLA-DR3/4. The strength of the association was similar in males and females, patients diagnosed before and after age 10 yr, and in Hispanics and NHWs. CONCLUSION: In this study, we confirm that PTPN22 is associated with T1D in the Colorado population.

Adolescent↗
PubMed2006

Genetic and functional evidence supporting SUMO4 as a type 1 diabetes susceptibility gene.

Genomewide linkage analyses since the early 1990s suggested over 20 genomic intervals that may contain susceptibility genes for type 1 diabetes. However, the identification of the specific genes in these intervals presents a formidable challenge due to a number of difficulties associated with genetic mapping and cloning of genes implicated in complex diseases. One of the difficulties is due to the presence of many weak and different susceptibility genes in different patients and populations, a phenomenon known as genetic heterogeneity. In 2004, we reported the cloning of a novel small ubiquitin-like modifier (SUMO) gene, SUMO4, in the IDDM5 interval on chromosome 6q25, and presented strong genetic and functional evidence suggesting that SUMO4 is a susceptibility gene for type 1 diabetes mellitus (T1DM). In this article, we will summarize genetic association data suggesting that SUMO4 is consistently associated with T1DM in the Asian populations while the association is more heterogeneous in the Caucasian populations. We will also discuss the possible molecular pathways through which sumoylation may regulate T1DM and autoimmunity.

Autoimmune Diseases↗
PubMed2006

TEDDY--The Environmental Determinants of Diabetes in the Young: an observational clinical trial.

The aim of the TEDDY study is to identify infectious agents, dietary factors, or other environmental agents, including psychosocial factors, which may either trigger islet autoimmunity, type 1 diabetes mellitus (T1DM), or both. The study has two end points: (a) appearance of islet autoantibodies and (b) clinical diagnosis of T1DM. Six clinical centers screen newborns for high-risk HLA genotypes. As of December 2005 a total of 54,470 newborns have been screened. High-risk HLA genotypes among 53,560 general population (GP) infants were 2576 (4.8%) and among 910 newborns with a first-degree relative (FDR) were 194 (21%). A total of 1061 children have been enrolled. The initial enrollment results demonstrate the feasibility of this complex and demanding a prospective study.

Adolescent↗
PubMed2006

Impaired Crkl expression contributes to the defective DNA binding of Stat5b in nonobese diabetic mice.

A point mutation in the Stat5b DNA binding domain in the nonobese diabetic (NOD) mouse was shown to have weaker DNA binding compared with the B6 Stat5b. Here, we assessed the binding ability of the mutant Stat5b in the B6 genetic background (B6.NOD-c11) and the wild-type Stat5b in the NOD background (NOD.Lc11). To our surprise, the binding ability of Stat5b is inconsistent with the presence or absence of the Stat5b mutation in these congenic mice but is correlated with the expression levels of the Crkl protein, which was coprecipitated by an anti-Stat5b antibody. Both the expression of Crkl and the Stat5b binding ability are the highest in B6.NOD-c11 and the lowest in NOD while intermediate in B6 and NOD.Lc11 mice. We demonstrated that the adapter molecule Crkl can bind Stat5b and that the Crkl protein is a Stat5b binding cofactor. More importantly, profection of Crkl recombinant protein significantly increased Stat5b binding ability and rescued the binding defect of the NOD mutant Stat5b, suggesting that Crkl is a key regulatory molecule for Stat5b binding. Therefore, the defective Crkl expression may contribute to the development of diabetes in the NOD mice by exacerbating the defective Stat5b binding ability.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Disordered osteoclast formation in RAGE-deficient mouse establishes an essential role for RAGE in diabetes related bone loss.

The mechanisms underlying diabetes-mediated bone loss are not well defined. It has been reported that the advanced glycation endproducts (AGEs) and receptor for AGEs (RAGEs) are involved in diabetic complications. Here, mice deficient in RAGE were used as a model for investigating the effects of RAGE on bone mass. We found that RAGE-/- mice have a significantly increased bone mass and bone biomechanical strength and a decreased number of osteoclasts compared to wild-type mice. The serum levels of IL-6 and bone breakdown marker pyridinoline were significantly decreased in RAGE-/- mice. RAGE-/- mice maintain bone mass following ovariectomy, whereas wild-type mice lose bone mass. Furthermore, osteoclast-like cells do express RAGE mRNA. Our data therefore indicate that RAGE serves as a positive factor to regulate the osteoclast formation, directly implicates a role for RAGE in diabetes-promoted bone destruction, and documents that the AGE-RAGE interaction may account for diabetes associated bone loss.

Animals↗
PubMed2005

Alterations of renal phenotype and gene expression profiles due to protein overload in NOD-related mouse strains.

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.

Animals↗
PubMed2005

Lack of correlation between the levels of soluble cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and the CT-60 genotypes.

BACKGROUND: Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) plays a critical role in downregulation of antigen-activated immune response and polymorphisms at the CTLA-4 gene have been shown to be associated with several autoimmune diseases including type-1 diabetes (T1D). The etiological mutation was mapped to the CT60-A/G single nucleotide polymorphism (SNP) that is believed to control the processing and production of soluble CTLA-4 (sCTLA-4). METHODS: We therefore determined sCTLA-4 protein levels in the sera from 82 T1D patients and 19 autoantibody positive (AbP) subjects and 117 autoantibody negative (AbN) controls using ELISA. The CT-60 SNP was genotyped for these samples by using PCR and restriction enzyme digestion of a 268 bp DNA segment containing the SNP. Genotyping of CT-60 SNP was confirmed by dye terminating sequencing reaction. RESULTS: Higher levels of sCTLA-4 were observed in T1D (2.24 ng/ml) and AbP (mean = 2.17 ng/ml) subjects compared to AbN controls (mean = 1.69 ng/ml) with the differences between these subjects becoming significant with age (p = 0.02). However, we found no correlation between sCTLA-4 levels and the CTLA-4 CT-60 SNP genotypes. CONCLUSION: Consistent with the higher serum sCTLA-4 levels observed in other autoimmune diseases, our results suggest that sCTLA-4 may be a risk factor for T1D. However, our results do not support the conclusion that the CT-60 SNP controls the expression of sCTLA-4.

Journal Article↗
PubMed2005

Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress.

The substrates of SUMO4, a novel member for the SUMO gene family, were characterized in HEK293 cells cultured under serum starvation by proteomic analysis. We identified 90 SUMO4 substrates including anti-stress proteins such as antioxidant enzymes and molecular chaperones or co-chaperones. The substrates also include proteins involved in the regulation of DNA repair and synthesis, RNA processing, protein degradation, and glucose metabolism. Several SUMO4-associated transcription factors were characterized by Western blot analyses. AP-1 was selected for in vitro conjugation assays to confirm SUMO4 sumoylation of these transcription factors. Further functional analyses of the transcription factors suggested that SUMO4 sumoylation represses AP-1 and AP-2alpha transcriptional activity, but enhances GR DNA binding capacity. These results demonstrate that SUMO4 sumoylation may play an important role in the regulation of intracellular stress.

Cell Line↗
PubMed2005

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.

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.

Animals↗
PubMed2005

SUMO wrestling with type 1 diabetes.

Post-translational modification of proteins by phosphorylation, methylation, acetylation, or ubiquitylation represent central mechanisms through which various biological processes are regulated. Reversible covalent modification (i.e., sumoylation) of proteins by the small ubiquitin-like modifier (SUMO) has also emerged as an important mechanism contributing to the dynamic regulation of protein function. Sumoylation has been linked to the pathogenesis of a variety of disorders including Alzheimer's disease (AD), Huntington's disease (HD), and type 1 diabetes (T1D). Advances in our understanding of the role of sumoylation suggested a novel regulatory mechanism for the regulation of immune responsive gene expression. In this review, we first update recent advances in the field of sumoylation, then specifically evaluate its regulatory role in several key signaling pathways for immune response and discuss its possible implication in T1D pathogenesis.

Amino Acid Sequence↗
PubMed2005

Mapping DNA-binding domains of the autoimmune regulator protein.

The human autoimmune regulator (AIRE) gene encodes a putative DNA-binding protein, which is mutated in patients affected by the autoimmune polyglandular syndrome type 1 or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. We have recently reported that AIRE can bind to two different DNA sequence motifs, suggesting the existence of at least two DNA-binding domains in the AIRE protein. By expressing a series of recombinant AIRE protein fragments, we demonstrate here that the two well-known plant homeodomains (PHD) domains in AIRE can bind to the ATTGGTTA sequence motif. The first ATTGGTTA-binding domain is mapped to amino acids 299-355 and the second ATTGGTTA-binding domain to amino acids 434-475. Furthermore, the SAND domain of AIRE is shown to bind to TTATTA motif. Results presented herein show that the residues at position 189-196 of AIRE (QRAVAMSS) are required for its binding to the TTATTA motif. The required sequence for DNA binding in the SAND domain of AIRE is remarkably different from other SAND-containing proteins such as Sp-100b and NUDR. Data presented in this paper indicate that the two PHD domains contained in AIRE, in addition to the SAND domain, can bind to specific DNA sequence motifs.

Base Sequence↗