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），目前正在全国范围内和世界范围内进行，以寻找1型糖尿病（T1 DM）的治愈方法。所有这些试验都是基于这样的理解，即在这些试验中，只有50%的T1 DM先证者的“高风险”一级亲属在5年随访时需要胰岛素。关于如何开发新的策略以提高多种标志物的敏感性，从而在T1 DM发作之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。到目前为止，仅基于传统的自身抗体标记物，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，我们证明了我们在应用基于蛋白质组学的技术来鉴定胰岛细胞抗体（伊卡）阳性T1 DM患者血清中与抗体反应的胰岛蛋白质方面的专业知识，但在对照血清中不具有反应性。到目前为止，我们已经确定了9个候选蛋白质组学技术认为值得研究的新的候选自身抗原在T1 DM。我们的数据还提供了间接证据，表明伊卡的一个重要子集可能与未鉴定的胰岛自身抗原反应。这些数据表明，在GAD 65/IA-2 AA阴性的新诊断T1 DM患者中存在一种新的伊卡亚群，并且伊卡亚群也可能与快速进展为需要胰岛素的糖尿病相关。对伊卡反应的进一步表征应有助于最终发现与快速进展为T1 DM相关的新型生化胰岛自身抗体标志物的合理方法。这一目标将首先利用基于蛋白质组学的技术（特定目标I），随后将结合我们在开发生化胰岛自身抗体检测方面的长期专业知识（特定目标II，III）。通过这种方法确定的新的替代标志物可能最终有助于监测对旨在延迟或逆转疾病过程的治疗的反应。

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.