Enhancement of Biomarkers for Type 1 Diabetes

描述(申请人提供)：这项拟议的研究基于我们过去8年的成果，将调查新的免疫生物标记物在同一地理区域患有和不患有T1 DM的T1 DM患者的第一级亲属中最大的基于人群的队列中的作用。国际合作临床研究网络正在进行越来越多的T1 DM的试点试验，例如TrialNet(：//www.DiabetesTrialNet.org)和免疫耐受网络(：//www.Immunetear ance.org)，以努力找到T1 DM的治疗方法。有许多正在筹备中的预防试验无法进行，因为目前可用的生物标记物无法确定参加这些试验的足够数量的个人。关于如何开发新的策略来提高多个标记物的敏感性并进而有效地招募一级亲属参加T1 DM预防试验，人们进行了无休止的讨论。根据我们最新的初步数据，目前应用的一个主要假设是，与传统的胰岛自身抗体标记物相比，检测针对IA-2、GAD65特异性表位的抗体和新发现的抗原ZnT8的新生物标记物的组合将进一步提高T1 DM进展的敏感性和预测价值。这项拟议的研究将在密歇根大学使用匹兹堡儿童医院的队列进行，该队列目前有161名一级亲属，他们在后续(转化者)中从10,000多名T1 DM先证者的亲属中转换为需要胰岛素的糖尿病。这一独特的血清样本档案是检验我们的免疫学假设的理想选择。这是所有中心中最多的转换器数量，因此，到下一个授权期结束时，应该有200多个转换器可用。由于不可能接触到T1 DM高危人群的胰腺组织和胰腺淋巴结，我们认为开发胰腺2细胞破坏的预测模型来了解致病T细胞反应在人类疾病自然发展过程中的作用是完全合适的。我们建立了数学模型，考虑了新的和传统的胰岛自身抗体生物标记物(特异性目标I)和高亲和力T细胞，它导致T1 DM进展过程中2细胞的破坏(特异性目标II)。我们将基于实验室的方法与T1 DM进展的数学模型结合起来，并组建了一支前所未有的免疫学研究和2细胞破坏的数学预测模型方面的领先专家团队。对T1 DM进展的关键因素(胰岛自身抗体、T细胞亲和力、内质网应激和UPR相互作用)进行建模很好地符合实验设计，并可能最终验证T细胞子集和/或UPR途径作为药物靶点，并被证明在指导治疗T1 DM的药物发现方面是有用的。拟议的研究结果应该允许开发新的生物标记物，对与T1 DM进展相关的关键因素进行建模，并促进旨在评估了解、预防和治疗1型糖尿病的新方法的重大临床试验。 公共卫生相关性：使用免疫流行病学研究可以可靠地识别胰岛自身抗体的最早迹象，这表明导致胰腺2细胞损伤的自身免疫过程已经启动。这些白细胞的出现很可能有助于胰腺2细胞的破坏过程，这是临床显性1型糖尿病的前奏。我们的研究具有重大的公共卫生意义，与1型糖尿病进展的关键因素的建模一起，这些研究还将提供一个概念框架，用于设计新的算法，用于在旨在预防1型糖尿病的重大临床试验中招募新的风险受试者。

DESCRIPTION (provided by applicant): The proposed research, based on our prior 8-year achievements, will investigate the role of new immunologic biomarkers in the largest population-based cohort of first degree relatives of T1DM patients with and without T1DM from the same geographical area. Growing number of pilot trials for T1DM are being conducted by international collaborative clinical research networks, such as TrialNet (://www.diabetestrialnet.org) and the Immune Tolerance Network (://www.immunetolerance.org) in an effort to find the cure for T1DM. There are many prevention trials in the pipeline that cannot be performed because the currently available biomarkers cannot identify a sufficient number of individuals to be enrolled in these trials. Endless discussions have taken place on how to develop new strategies to enhance sensitivity of multiple markers and in turn effectively enroll first-degree relatives in T1DM prevention trials. Based on our most recent preliminary data, a major hypothesis of the present application is that a combination of novel biomarkers detecting antibodies directed to IA-2, GAD65 specific epitopes and the newly discovered antigen ZnT8 will further enhance sensitivity and the predictive value of T1DM progression as compared to conventional islet autoantibody markers. The proposed research will be performed at the University of Michigan using the Children's Hospital of Pittsburgh cohort, which currently has 161 first degree relatives, who converted to insulin-requiring diabetes during follow-up (converters) from a pool of over 10,000 relatives of T1DM probands. This unique serum sample archive is ideal to test our immunologic hypotheses. This represents the largest number of converters of any center and as such, more than 200 converters should be available by the end of the next grant period. Because it is impossible to have access to pancreatic tissue and pancreatic lymph nodes from subjects at risk of developing T1DM, we feel that it is entirely appropriate to develop predictive models of pancreatic 2 cell destruction to understand the role of pathogenic T cell responses during the natural history of human disease. We have constructed mathematical models taking into consideration new and conventional islet autoantibody biomarkers (Specific Aim I) and high avidity T cells which leads to 2 cell destruction during T1DM progression (Specific Aim II). We have coupled laboratory-based methodology with mathematical modeling of T1DM progression and have assembled an unprecedented team of leading experts in immunology research and mathematical predictive models of 2 cell destruction. Modeling key elements of T1DM progression (islet autoantibodies, T cell avidity, ER stress and UPR interactions) fits well with the experimental design and may ultimately validate a subset of T cells and/or the UPR pathway as drug targets and prove useful in guiding drug discovery to treat T1DM. The outcome of the proposed investigation should allow for the development of new biomarkers, modeling of key elements associated with T1DM progression and facilitate major clinical trials aimed at evaluating new approaches for understanding, preventing and treating Type 1 diabetes. PUBLIC HEALTH RELEVANCE: The use of immuno-epidemiology studies can be applied to reliably identify the earliest signs of islet autoantibodies which indicate that the autoimmune process leading to pancreatic 2 cell injury has already initiated. It is likely that the appearance of these white cells contribute to the destructive process of pancreatic 2 cells, a prelude of clinically overt Type 1 diabetes mellitus. Our research has major public health implications and together with modeling of key elements of Type 1 diabetes progression these studies will also provide a conceptual framework for designing new algorithms used for enrolling new subjects at risk in major clinical trials aimed at preventing Type 1 diabetes.