Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have identified a susceptibility region for insulin-dependent (type 1) diabetes mellitus on chromosome 11q13 (IDDM4). In this study, 15 polymorphic markers were analyzed for 382 affected sibpair (ASP) families with type 1 diabetes. Our analyses provided additional evidence for linkage for IDDM4 (a peak LOD score of 3.4 at D11S913). The markers with strong linkage evidence are located within an interval of approximately 6 cM between D11S4205 and GALN. We also identified polymorphisms in two candidate genes, Fas-associated death domain protein (FADD) and galanin (GALN). Analyses of the data by transmission/disequilibrium test (TDT) and extended TDT (ETDT) did not provide any evidence for association/linkage with these candidate genes. However, ETDT did reveal significant association/linkage with the marker D11S987 (P=0.0004) within the IDDM4 interval defined by ASP analyses, suggesting that IDDM4 may be in the close proximity of D11S987.
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PMID:Fine-mapping of the type 1 diabetes locus (IDDM4) on chromosome 11q and evaluation of two candidate genes (FADD and GALN) by affected sibpair and linkage-disequilibrium analyses. 1098 76

In type 1 diabetes, many effector mechanisms damage the beta cell, a key one being perforin/granzyme B production by CD8(+) T cells. The death receptor pathway has also been implicated in beta cell death, and we have therefore generated NOD mice that express a dominant-negative form of the Fas-associated death domain protein (FADD) adaptor to block death receptor signaling in beta cells. Islets developed normally in these animals, indicating that FADD is not necessary for beta cell development as it is for vasculogenesis. beta cells from the transgenic mice were resistant to killing via the Fas pathway in vitro. In vivo, a reduced incidence of diabetes was found in mice with higher levels of dominant-negative FADD expression. This molecule also blocked signals from the IL-1R in culture, protecting isolated islets from the toxic effects of cytokines and also marginally reducing the levels of Fas up-regulation. These data support a role for death receptors in beta cell destruction in NOD mice, but blocking the perforin/granzyme pathway would also be necessary for dominant-negative FADD to have a beneficial clinical effect.
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PMID:Transgenic expression of dominant-negative Fas-associated death domain protein in beta cells protects against Fas ligand-induced apoptosis and reduces spontaneous diabetes in nonobese diabetic mice. 1597 61

IDDM results from pancreatic beta cell destruction by islet-reactive T cells, a process that involves beta cell apoptosis. Fas-FasL pathway plays a major role in pancreatic beta cell death. Fas-associated death domain protein (FADD), the component of the tumor necrosis factor receptor type 1 (TNFR1) and Fas signaling complexes, is involved in TNFR1- and Fas-induced apoptosis. Inhibiting the function of FADD will lead to blocking downstream apoptosis signal, which protects pancreatic beta cells from destruction by Fas-FasL pathway. In this study we constructed eukaryotic expressing vector of fusional protein FADDdel-GFP named pFADDdel-GFP. After pFADDdel-GFP was transfected into NIT, the expression of FADDdel-GFP in NIT was detected by fluorescence microscopy and the resistance of NIT transfected with pFADDdel-GFP to cytotoxicity mediated by special T cells was detected by FACS and MTT. The results showed that NIT modified by pFADDdel-GFP obviously resisted cytotoxicity mediated by special T cells. Therefore, it may be useful in the prevention or treatment of IDDM by intervening Fas-FasL pathway.
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PMID:FADDdel-GFP modified mouse insulinoma cells counteract the cytotoxicity of reactive T cells. 1628 99

Islet transplantation is considered a therapeutic option for type 1 diabetes (T1D). However, allorejection is one major barrier for the successful islet transplantation. In the present study, we have tested the feasibility of a deletion construct for Fas-associated death domain protein (FADD; without the death effecter domain) fused with green fluorescent protein (FADDdel-GFP) for blocking the Fas-FasL signaling pathway in prevention of transplanted beta cell destruction by allo-rejection in T1D. In vitro studies have shown that NIT-1 cells with ectopic FADDdel expression were resistant to cytokine-induced apoptosis and CTL-mediated lysis. Diabetic Balb/c mice reached normoglycemia promptly and gained weight after transplantation of NIT-1 cells with ectopic FADDdel-GFP expression. These recipients showed a significant longer survival time than that of recipients transplanted with NIT cells with ectopic GFP expression only. Our results together suggest that FADDdel could be a useful target for the improvement of islet transplantation for T1D.
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PMID:Transplantation of NIT-1 cells with ectopic FADDdel-GFP expression for treatment of streptozotocin-induced diabetes. 1981 Dec 59