Proteomics of Autoimmune Type 1 Diabetes

描述（由申请人提供）：越来越多的试点试验，如TrialNet (http://www.niddk.nih.gov/welcome/releases/06-05-04.htm)，目前正在全国和世界范围内开展，以寻找1型糖尿病（T1DM）的治疗方法。所有这些试验都是基于这样一种认识，即参加这些试验的T1DM先发者的“高风险”一级亲属中，只有50%在5年随访时需要胰岛素。关于如何制定新的策略来提高多种标记物的敏感性，并在T1型糖尿病发病前有效地将一级亲属纳入此类试验，已经进行了无休止的讨论。截至目前，仅基于传统的自身抗体标记，全国范围内这些亲属的数量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学的技术鉴定胰岛蛋白与胰岛细胞抗体（ICA）阳性T1型糖尿病患者血清中抗体反应的专业知识，而不是在对照组血清中。迄今为止，我们已经通过蛋白质组学技术鉴定出9种候选蛋白，认为值得作为T1DM新的候选自身抗原进行研究。我们的数据也为ICA的一个重要亚群的存在提供了间接证据，该亚群可能与未识别的胰岛自身抗原发生反应。这些数据表明，GAD65/IA-2 AA阴性新诊断的T1DM患者中存在一种新的ICA亚群，并且ICA亚群也可能与胰岛素需用糖尿病的快速进展有关。对这种ICA反应的进一步表征应该有助于找到一种合理的方法，最终发现与T1DM快速进展相关的新的生化胰岛自身抗体标记物。这一目标最初将利用基于蛋白质组学的技术（Specific Aim I），随后将与我们在开发生化胰岛自身抗体检测方面的长期专业知识相结合（Specific Aims II， III）。通过这种方法鉴定的新的替代标记物可能最终有助于监测旨在延缓或逆转疾病过程的治疗反应。

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.