Proteomics of Autoimmune Type 1 Diabetes

描述(申请人提供)：越来越多的试点试验，如Trialnet(http://www.niddk.nih.gov/welcome/releases/06-05-04.htm)，，现正在全国和世界范围内进行，以努力寻找1型糖尿病(T1 DM)的治疗方法。所有这些试验都是基于这样一种理解，即在这些试验中登记的T1 DM先证者的“高风险”一级亲属中，只有50%在5年的随访中出现了胰岛素需求。关于如何开发新的策略来提高多个标记物的敏感性，进而在T1 DM发病之前有效地招募一级亲属参加这样的试验，已经有了无休止的讨论。截至今天，仅凭传统的自身抗体标记物，全国范围内这些亲属的数量将不足以完成所有拟议的临床试验。在初步研究中，我们展示了我们在应用基于蛋白质组的技术来鉴定与胰岛细胞抗体(ICA)阳性的T1 DM患者血清中的抗体反应而不是与对照组血清中的抗体反应的胰岛蛋白方面的专长。到目前为止，我们已经通过蛋白质组学技术确定了9个值得研究的候选蛋白，作为T1 DM新的候选自身抗原。我们的数据还提供了间接证据，证明存在ICA的一个重要子集，该子集可能与未知的胰岛自身抗原发生反应。这些数据表明，在GAD65/IA-2 AA阴性的新诊断的T1糖尿病患者中存在一个新的ICA亚群，并且ICA亚群也可能与快速进展为需要胰岛素的糖尿病有关。对这种ICA反应的进一步表征应该有助于合理的方法最终发现与快速进展到T1 DM相关的新的生化胰岛自身抗体标记物(S)。这一目标最初将使用基于蛋白质组的技术(特定目标I)来开发，随后将与我们在开发生化胰岛自身抗体分析(特定目标II、III)方面的长期专业知识相结合。通过这种方法确定的新的替代标记物最终可能有助于监测旨在延迟或逆转疾病进程的治疗的反应。

DESCRIPTION (provided by applicant): A growing number of pilot trials, such as TrialNet (http://www.niddk.nih.gov/welcome/releases/06-05-04.htm), are now being carried out nationwide and worldwide in an effort to find the cure for Type 1 diabetes (T1DM). All of these trials are based on the understanding that only 50% of "high risk" first-degree relatives of T1DM probands enrolled in these trials develop insulin requirement at 5 year follow-up. 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 into such trials prior to T1 DM onset. As of today, based on conventional autoantibody markers alone, the number of these relatives nationwide would be insufficient to complete all the proposed clinical trials. In the Preliminary Studies we demonstrate our expertise in applying a proteomic-based technology to identify pancreatic islet proteins reactive with antibodies in the sera of islet cell antibody (ICA) positive T1 DM patients but not in the sera of controls. To date, we have identified 9 candidate proteins by proteomic technology deemed worthy of investigation as new candidate autoantigens in T1DM. Our data also provide indirect evidence for the presence of an important subset of ICA that likely reacts with unidentified islet autoantigens. These data suggest that a novel subset of ICA is present in GAD65/IA-2 AA negative newly diagnosed T1DM patients and that a subset of ICA might also be related with rapid progression to insulin-requiring diabetes. A further characterization of this ICA response should facilitate a rational approach to ultimately discover a novel biochemical islet autoantibody marker(s) associated with rapid progression to T1DM. This objective will be initially exploited using proteomic-based technology (Specific Aim I) and this approach will subsequently be coupled with our longstanding expertise in developing biochemical islet autoantibody assays (Specific Aims II, III). Novel surrogate markers that will be identified by this approach might ultimately aid in monitoring the response to therapy aimed at delaying or reversing the disease process.