Proteomics of Autoimmune Type 1 Diabetes

自身免疫 1 型糖尿病的蛋白质组学

• 批准号: 7276363
• 负责人: MASSIMO T PIETROPAOLO
• 金额: $ 19.05万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-25 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7276363
• 关键词: autoantibody; autoantigens; biomarker; biotechnology; clinical research; diabetes mellitus genetics; diabetes risk; diagnosis design /evaluation; diagnostic tests; family genetics; genetic susceptibility; human genetic material tag; human subject; immunogenetics; insulin dependent diabetes mellitus; isoelectric point; mass spectrometry; method development; molecular cloning; molecular weight; nucleic acid sequence; pancreatic islets; proteomics; radioimmunoassay; two dimensional gel electrophoresis; western blottings

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.

描述（由申请人提供）：越来越多的试点试验，例如 TrialNet (http://www.niddk.nih.gov/welcome/releases/06-05-04.htm)，目前正在全国和全世界范围内进行，以期找到 1 型糖尿病 (T1DM) 的治疗方法。所有这些试验均基于以下认识：参与这些试验的 T1DM 先证者的“高风险”一级亲属中，只有 50% 在 5 年随访时出现胰岛素需求。关于如何开发新策略来增强多种标志物的敏感性并进而在 T1 DM 发病前有效地将一级亲属纳入此类试验的讨论一直在进行。截至目前，仅根据传统的自身抗体标记物，全国范围内这些亲属的数量还不足以完成所有拟议的临床试验。在初步研究中，我们展示了应用基于蛋白质组学的技术来识别与胰岛细胞抗体 (ICA) 阳性 T1 DM 患者血清中的抗体发生反应的胰岛蛋白的专业知识，但在对照血清中则不然。迄今为止，我们已经通过蛋白质组学技术鉴定了 9 种候选蛋白，认为值得研究作为 T1DM 中新的候选自身抗原。我们的数据还为 ICA 的一个重要子集的存在提供了间接证据，该子集可能与未识别的胰岛自身抗原发生反应。这些数据表明，新诊断的 GAD65/IA-2 AA 阴性 T1DM 患者中存在一个新的 ICA 亚型，并且 ICA 的一个亚型也可能与快速进展为需要胰岛素的糖尿病有关。对该 ICA 反应的进一步表征应有助于采取合理的方法，最终发现与 T1DM 快速进展相关的新型生化胰岛自身抗体标记物。该目标最初将使用基于蛋白质组学的技术（具体目标 I）来实现，随后该方法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（具体目标 II、III）。通过这种方法鉴定的新型替代标记可能最终有助于监测旨在延迟或逆转疾病进程的治疗的反应。