Identification of predictive marker for type 1 diabetes development using GAD antibody epitope analysis and its application to disease prevention
| Project/Area Number |
15590947
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Nagasaki University |
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Principal Investigator |
KAWASAKI Eiji Nagasaki University Hospital of Medicine and Dentistry, Department of Metabolism/Diabetes and Clinical Nutrition, Associate Professor, 医学部・歯学部附属病院, 助教授 (70336171)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2003: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | Autoimmunity / Autoantibody / Autoantigen / Diabetes / Epitope / Prediction |
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| Research Abstract |
Although the majority of patients with type 1 diabetes are young, lean, and ketosis-prone, there are number of patients with type 1 diabetes initially diagnosed as having type 2 diabetes at disease onset called LADA(Latent Autoimmune Diabetes in Adults). These patients with LADA often progress toward insulin-deficient state within several years after diagnosis. Although the high titer of GAD autoantibodies is a predictive marker of insulin dependency in LADA patients, there is a certain number of patients with high titer of GAD autoantibodies who do not progressed to insulin dependency for many years. In our cross-sectional study on the clinical evaluation of non-insulin dependent diabetic patients with GAD autoantibodies, approximately two-thirds of LADA patients progress toward insulin deficiency (positive predictive value 67.1 %). Therefore, to establish the better predictive marker for insulin deficiency in LADA patients, the fine mapping of GAD65 autoantibody epitope recognition was conducted. Chimeric molecules were generated by substitution of regions of human GAD65 with homologous regions of GAD67,an isoform of GAD that is not a major autoantigen in type 1 diabetes. We have created the six GAD65/67 chimeric constructs designated GAD65-N/GAD67-MC、GAD65-NM/GAD67-C、GAD65-N/GAD67-M/GAD65-C、GAD67-N/GAD65-MC、GAD67-NM/GAD65-C、GAD67-N/GAD65-M/GAD67-C. Serum reactivity to a series of GAD constructs were determined by radioligand binding assays in a 96-well assay format. With competition by recombinant GAD67 protein, two major epitopes recognized by GAD65-specific autoantibodies were found, designated Epitope 1(E1,aa 245-360) and Epitope 2(E2,aa 443-585), in sera from patients with type 1 diabetes and LADA. Now the nation-wide prospective study is underway to identify the GAD65 autoantibody epitope(s) for prediction of insulin dependency in LADA patients.
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Report
(3 results)
Research Products
(7 results)
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[Journal Article] Epitope Analysis of GAD65 Autoantibodies in Japanese Patients with Autoimmune Diabetes2003
Author(s)
E.Kawasaki, N.Abiru, A.Ide, F.Sun, T.Fukushima, R.Takahashi, H.Kuwahara, N.Fujita, A.Kita, K.Oshima, S.Uotani, H.Yamasaki, Y.Yamaguchi, K.Eguchi
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Journal Title
Ann NY Acd Sci 1005
Pages: 440-448
Description
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