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）：越来越多的试验试验，例如试用网（http://www.niddk.nih.nih.gov/welcome/welcome/releases/06-05-044.htm）现在正在全国范围内和全球进行努力，以寻找1型糖尿病的疗效。所有这些试验都基于这样的理解，即参加这些试验的T1DM检验的“高风险”一级亲戚中只有50％在5年随访时会产生胰岛素要求。关于如何制定新策略以增强多个标记的灵敏度，进而有效地将一级亲戚招募到T1 DM发作之前的试验中，进行了无尽的讨论。截至今天，仅基于常规的自身抗体标记，全国这些亲戚的数量将不足以完成所有提出的临床试验。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方面的专业知识来鉴定胰岛细胞抗体（ICA）阳性T1 DM患者的抗体反应性的胰岛胰岛蛋白，但在对照血清中却没有。迄今为止，我们已经通过蛋白质组学技术值得调查确定了9种候选蛋白，在T1DM中是新的候选自动抗原。我们的数据还为存在重要的ICA子集的存在提供了间接证据，ICA可能与身份不明的胰岛自身抗原反应。这些数据表明，GAD65/IA-2 AA阴性新诊断为T1DM患者的ICA的新型ICA子集存在，并且ICA的子集也可能与迅速发展到胰岛素优质糖尿病有关。这种ICA响应的进一步表征应促进一种理性方法，最终发现与快速发展为T1DM相关的新型生化胰岛自身抗体标记。最初将使用基于蛋白质组学的技术来利用这一目标（特定目的I），随后将与我们在开发生化胰岛自动抗体测定方面的长期专业知识相结合（特定目标II，III）。这种方法将通过这种方法确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过程的治疗反应。